VCV000017967.93 - ClinVar

NM_001127701.1(SERPINA1):c.1096G>A (p.Glu366Lys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(49)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic; risk factor

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of a Haplotype

NM_000295.4(SERPINA1):c.[1096G>A;35T>C]

Identifiers

NM_001127701.1(SERPINA1):c.1096G>A (p.Glu366Lys)

Variation ID: 17967 Accession: VCV000017967.93

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q32.13 14: 94378610 (GRCh38) [ NCBI UCSC ] 14: 94844947 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2014	Nov 24, 2024	Oct 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000295.5:c.1096G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000286.3:p.Glu366Lys	missense
NM_001002235.3:c.1096G>A	NP_001002235.1:p.Glu366Lys	missense
NM_001002236.3:c.1096G>A	NP_001002236.1:p.Glu366Lys	missense
NM_001127700.2:c.1096G>A	NP_001121172.1:p.Glu366Lys	missense
NM_001127701.2:c.1096G>A	NP_001121173.1:p.Glu366Lys	missense
NM_001127702.2:c.1096G>A	NP_001121174.1:p.Glu366Lys	missense
NM_001127703.2:c.1096G>A	NP_001121175.1:p.Glu366Lys	missense
NM_001127704.2:c.1096G>A	NP_001121176.1:p.Glu366Lys	missense
NM_001127705.2:c.1096G>A	NP_001121177.1:p.Glu366Lys	missense
NM_001127706.2:c.1096G>A	NP_001121178.1:p.Glu366Lys	missense
NM_001127707.2:c.1096G>A	NP_001121179.1:p.Glu366Lys	missense
NC_000014.9:g.94378610C>T
NC_000014.8:g.94844947C>T
NG_008290.1:g.17083G>A
LRG_575:g.17083G>A
LRG_575t1:c.1096G>A	LRG_575p1:p.Glu366Lys
	P01009:p.Glu366Lys

... more HGVS ... less HGVS

Protein change

E366K

Other names

E342K
Z allele
PI Z(AUGSBURG)
PI Z(TUN)
PI*Z
SERPINA1, GLU342LYS ON M1A
SERPINA1, GLU342LYS ON M2
Z
p.E366K

Canonical SPDI

NC_000014.9:94378609:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

effect on catalytic protein function; Variation Ontology [ VariO:0008]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00399 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00399

1000 Genomes Project 30x 0.00437

Exome Aggregation Consortium (ExAC) 0.01170

Trans-Omics for Precision Medicine (TOPMed) 0.01171

The Genome Aggregation Database (gnomAD) 0.01282

Links

ClinGen: CA127676 Genetic Testing Registry (GTR): GTR000006840 Genetic Testing Registry (GTR): GTR000500899 Genetic Testing Registry (GTR): GTR000591284 UniProtKB: P01009#VAR_007004 OMIM: 107400.0011 OMIM: 107400.0028 dbSNP: rs28929474 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SERPINA1		-	-	GRCh38 GRCh38 GRCh37	484	519

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Alpha-1-antitrypsin deficiency	Pathogenic (27)	criteria provided, multiple submitters, no conflicts	Oct 9, 2024	RCV000148877.59
FRAXE	Pathogenic (1)	no assertion criteria provided	Jul 29, 2014	RCV000194811.9
See cases	Pathogenic (1)	criteria provided, single submitter	Oct 6, 2020	RCV002251912.9
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Apr 5, 2017	RCV000623762.11
Susceptibility to severe coronavirus disease (COVID-19)	Uncertain significance (1)	no assertion criteria provided	May 13, 2022	RCV002466247.8
PI Z(TUN)	other (1)	no assertion criteria provided	Dec 1, 1994	RCV000019595.12
PI Z	other (1)	no assertion criteria provided	Jul 15, 2016	RCV000019567.12
PI Z(AUGSBURG)	other (1)	no assertion criteria provided	Dec 1, 1994	RCV000019594.12
Chronic obstructive pulmonary disease	risk factor (1)	criteria provided, single submitter	Mar 4, 2020	RCV001195107.13
not provided	Pathogenic (11)	criteria provided, multiple submitters, no conflicts	Jul 21, 2024	RCV000255454.49
Alpha-1-antitrypsin deficiency COPD, severe early onset	Pathogenic (1)	criteria provided, single submitter	Aug 31, 2020	RCV002054450.9
Neurodevelopmental disorder	Pathogenic (1)	criteria provided, single submitter	Dec 16, 2021	RCV002276567.8
SERPINA1-related disorder	Pathogenic (1)	no assertion criteria provided	Sep 6, 2024	RCV003415721.6
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 27, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: no Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Study: CSER-NextGen Accession: SCV000538061.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017	Comment: In homozygous state this variant is the majorcause of severe alpha-1 antitrypsin deficiency (95%) and the mutant protein level is only 10-15% of the normal … (more) In homozygous state this variant is the majorcause of severe alpha-1 antitrypsin deficiency (95%) and the mutant protein level is only 10-15% of the normal protein (less)
Pathogenic (May 08, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000230899.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018	Publications: PubMed (2) PubMed: 17964515‚ 8970361 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SERPINA1 https://www.ncbi.nlm.nih.gov/boo… https://www.ncbi.nlm.nih.gov/books/NBK1519/ Number of individuals with the variant: 194 Zygosity: Homozygote, Single Heterozygote Sex: mixed
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001139501.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020
risk factor (Mar 04, 2020)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Chronic obstructive pulmonary disease Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000200303.6 First in ClinVar: Jan 30, 2015 Last updated: Jul 06, 2020	Publications: PubMed (14) PubMed: 9195389‚ 21960536‚ 26987331‚ 26831755‚ 14522813‚ 26672964‚ 26304913‚ 15454649‚ 22912729‚ 26243289‚ 24518491‚ 22971141‚ 24428606‚ 21637600 Comment: SERPINA1 c.1096G>A (p.Glu366Lys, commonly known as Z allele or PiMZ) has been associated with increased risk for chronic obstructive pulmonary disease (COPD). This variant has … (more) SERPINA1 c.1096G>A (p.Glu366Lys, commonly known as Z allele or PiMZ) has been associated with increased risk for chronic obstructive pulmonary disease (COPD). This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of European non-Finnish ancestry (1.8%, Genome Aggregation Database (gnomAD); rs28929474) and is present in ClinVar (ID: 17967). Large meta-analyses have reported odds ratios of 2.31-3.54 (OR= 2.31 95% CI [1.60-3.35], Hersh 2004, OR=3.54 95% CI [2.14-5.85] Topic 2012) developing COPD in individuals who are heterozygous for this variant. In vitro functional studies provide some evidence that the p.Glu366Lys variant may impact protein function (Fregonese 2008). In summary, this variant is an established risk factor for COPD. SERPINA1 c.1096G>A (p.Glu366Lys, commonly known as Z allele or PiZZ and historically reported as p.Glu342Lys) has been associated with increased risk for chronic obstructive pulmonary disease (COPD). This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of European non-Finnish ancestry (1.8%, Genome Aggregation Database (gnomAD); rs28929474) and is present in ClinVar (ID: 17967). A large meta-analysis has reported an odds ratio of 42.42 [95% CI 4.41â€“332.55] (Topic 2012) for developing COPD in individuals who are homozygous for this variant. In vitro functional studies provide some evidence that the p.Glu366Lys variant may impact protein function (Fregonese 2008). In summary, this variant is an established risk factor for COPD. (less) Number of individuals with the variant: 13
Pathogenic (Dec 26, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001194095.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (3) PubMed: 3264419‚ 18515255‚ 3484754 Comment: NM_000295.4(SERPINA1):c.1096G>A(E366K, aka Z allele) is classified as pathogenic in the context of alpha-1 antitrypsin deficiency. Sources cited for classification include the following: PMID 3264419, 18515255 … (more) NM_000295.4(SERPINA1):c.1096G>A(E366K, aka Z allele) is classified as pathogenic in the context of alpha-1 antitrypsin deficiency. Sources cited for classification include the following: PMID 3264419, 18515255 and 3484754. Classification of NM_000295.4(SERPINA1):c.1096G>A(E366K, aka Z allele) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (Aug 31, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alpha-1-antitrypsin deficiency Chronic obstructive pulmonary disease Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV002495950.1 First in ClinVar: Apr 12, 2022 Last updated: Apr 12, 2022	Comment: SERPINA1 NM_000295.4 exon 5 p.Glu366Lys (c.1096G>A): This variant, also referred to in the literature as Glu342Lys, is commonly known as the Z allele and is … (more) SERPINA1 NM_000295.4 exon 5 p.Glu366Lys (c.1096G>A): This variant, also referred to in the literature as Glu342Lys, is commonly known as the Z allele and is responsible for a large majority of cases of alpha-1-antitrypsin deficiency (A1ATD). It has been reported in the literature in the homozygous state in numerous individuals with severe A1ATD (Brantly 1991 PMID:1889260, Calapoglu 2009 PMID:19083091, Pan 2009 PMID:19444872, Ferrarotti 2012 PMID:22426792, Schaefer 2015 PMID:26310624). In the heterozygous state, it is reported to be a risk factor for COPD, emphysema, and liver disease (Bartlett 2009 PMID:19738092, Ferrarotti 2012 PMID:22426792, Thun 2012 PMID:22912729, Li 2018 PMID:30068317). This variant is also present in 2.1% (1356/64560) of European alleles in the Genome Aggregation Database, including 41 homozygotes (https://gnomad.broadinstitute.org/variant/14-94378610-C-T?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:17967). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown that this variant leads to misfolding and accumulation of protein in hepatocyte endoplasmic reticulum. (Pan 2009 PMID:19444872, Kass 2012 PMID:22735536, Hughes 2013 PMID:25181470). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above. (less)
Pathogenic (Oct 06, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	See cases Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002523807.1 First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022	Comment: ACMG classification criteria: PS3, PS4, PM3 Clinical Features: Gastrointestinal inflammation (present) , Diarrhea (present) , Anemia (present) Geographic origin: Brazil
Pathogenic (Dec 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodevelopmental disorder Affected status: yes Allele origin: germline	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes Accession: SCV002564459.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022
Pathogenic (Aug 31, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002572444.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (15) PubMed: 15978931‚ 24592811‚ 32699024‚ 23632999‚ 1889260‚ 9569237‚ 22426792‚ 27246852‚ 25181470‚ 3500183‚ 12034572‚ 20301692‚ 22933512‚ 34408828‚ 34408829 Comment: Variant summary: SERPINA1 (formerly known as PI) c.1096G>A (p.Glu366Lys; aka Glu342Lys) results in a conservative amino acid change in the encoded protein sequence. Four of … (more) Variant summary: SERPINA1 (formerly known as PI) c.1096G>A (p.Glu366Lys; aka Glu342Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.011 in 251360 control chromosomes, predominantly at a frequency of 0.018 within the European subpopulation in the gnomAD database, including 17 homozygotes. Although the variant reaches polymorphic frequencies in Caucasians, this occurrence is consistent with the disease prevalence (see e.g. Stoller_2005, de Serres_2012, Blanco_2020). The variant, c.1096G>A (commonly known as the Z allele, or PI*Z allele) is reported as the most frequent alpha-1 antitrypsin deficiency allele, and individuals who are homozygous for the variant are at high risk for both lung- and liver disease, reportedly with 80-100% risk for developing emphysema (see e.g. Brantly_1991, Stoller_2005, Bornhorst_2013, Ferrarotti_2012, Stoller_2020, Tejwani_2021, Patel_2021). While nonsmoking heterozygotes are generally not considered to be at significantly increased risk for lung disease, smoking heterozygotes are at increased risk for COPD (Stoller_2020, Tejwani_2021). Several publications reported loss-of-function mechanism for the variant, i.e. homozygous individuals have a serum concentration of alpha-1 antitrypsin (AAT) that is approximately 10%-20% of normal, and the ability of the variant protein to inhibit neutrophil elastase is also decreased (e.g. Ogushi_1987, Bornhorst_2013). In addition, several studies also reported a gain-of-function mechanism for the variant, demonstrating that it can form (toxic) intracellular aggregates, and extracellular polymers with chemotactic properties for neutrophils, resulting in an exacerbated proinflammatory phenotype, especially in response to cigarette smoke (e.g. Elliott_1998, Parmar_2002, Alam_2014). 23 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Feb 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893353.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Nov 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003806738.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PS3 supporting, PM3 very strong, PP4 Number of individuals with the variant: 1 Clinical Features: Hepatic fibrosis (present) , Hydrocele testis (present) , Congenital hepatic fibrosis (present) , Reduced circulating alpha-1-antitrypsin concentration (present) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Mar 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alpha-1-antitrypsin deficiency Alpha-1-antitrypsin deficiency Alpha-1-antitrypsin deficiency Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV003920463.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023	Comment: SERPINA1 NM_000295.4 exon 5 p.Glu366Lys (c.1096G>A): This variant, also referred to in the literature as Glu342Lys, is commonly known as the Z allele and is … (more) SERPINA1 NM_000295.4 exon 5 p.Glu366Lys (c.1096G>A): This variant, also referred to in the literature as Glu342Lys, is commonly known as the Z allele and is responsible for a large majority of cases of alpha-1-antitrypsin deficiency (A1ATD). It has been reported in the literature in the homozygous state in numerous indivdiuals with severe A1ATD (Brantly 1991 PMID:1889260, Calapoglu 2009 PMID:19083091, Pan 2009 PMID:19444872, Ferrarotti 2012 PMID:22426792, Schaefer 2015 PMID:26310624). In the heterozygous state, it is reported to be a risk factor for COPD, emphysema, and liver disease (Bartlett 2009 PMID:19738092, Ferrarotti 2012 PMID:22426792, Thun 2012 PMID:22912729, Li 2018 PMID:30068317). This variant is also present in 2.1% (1356/64560) of European alleles in the Genome Aggregation Database, including 41 homozygotes (https://gnomad.broadinstitute.org/variant/14-94378610-C-T?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:17967). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown that this variant leads to misfolding and accumulation of protein in hepatocyte endoplasmic reticulum. (Pan 2009 PMID:19444872, Kass 2012 PMID:22735536, Hughes 2013 PMID:25181470). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above. (less)
Pathogenic (Oct 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: yes Allele origin: germline	Clinical Genomics Laboratory, Washington University in St. Louis Accession: SCV004177078.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: The SERPINA1 c.1096G>A (p.Glu366Lys) variant, also known as Gly342Lys or more commonly the Z allele, has been reported in the homozygous and compound heterozygous state … (more) The SERPINA1 c.1096G>A (p.Glu366Lys) variant, also known as Gly342Lys or more commonly the Z allele, has been reported in the homozygous and compound heterozygous state in individuals with alpha1-antitrypsin deficiency and is reported as the most common pathogenic variant (Bornhorst JA et al., PMID: 23632999; Calapoğlu et al., PMID: 19083091; Stoller JK et al., PMID: 20301692; Stoller JK and Aboussouan LS, PMID: 21960536). While this variant rarely leads to alpha1-antitrypsin deficiency in heterozygous individuals, individuals that carry this variant in the heterozygous state have an increased risk for developing chronic obstructive pulmonary disease or liver disease (OR: 2.31-7.3; Hersh CP et al., PMID: 15454649; Strnad P et al., PMID: 30068662; Topic A et al., PMID: 22971141). This variant has been reported in the ClinVar database as a germline risk factor or pathogenic variant by many submitters. The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 1.8% in the European (non-Finnish) population which is not inconsistent with the prevalence of alpha1-antitrypsin deficiency (Brode SK et al., PMID: 22761482). The amino acid at this position is critical for protein function (Huang X et al., PMID: 27246852) and computational predictors indicate that the variant is damaging, evidence that correlates with impact to SERPINA1 function. In support of this prediction, functional studies show this variant leads to an accumulation of the protein leading to liver damage, indicating that this variant impacts protein function (Dycaico MJ et al., PMID: 3264419; Lomas DA et al., PMID: 1608473). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. (less)
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000630386.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (11) PubMed: 28492532‚ 15978931‚ 22426792‚ 23632999‚ 1889260‚ 22933512‚ 3500183‚ 9569237‚ 12034572‚ 22735536‚ 25181470 Comment: This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 366 of the SERPINA1 protein … (more) This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 366 of the SERPINA1 protein (p.Glu366Lys). This variant is present in population databases (rs28929474, gnomAD 1.8%), and has an allele count higher than expected for a pathogenic variant. This variant, also referred to as PI*Z allele or Z allele, is a well known cause of severe alpha-1 antitrypsin (AAT) deficiency in the literature (PMID: 15978931, 22426792, 23632999, 1889260). It is associated with an 80%-100% risk of developing emphysema when it is found in the homozygous state, and a 20-50% risk when it is found as a compound heterozygote with the S allele (PMID: 15978931, 22933512). This variant is also known as p.Glu342Lys in the literature. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17967). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SERPINA1 protein function. Experimental studies have shown that this missense change is five times less effective than the normal M allele as an inhibitor of neutrophil elastase and it forms polymers in the lung that can be chemoattractants for neutrophils, thereby increasing inflammation (PMID: 3500183, 9569237, 12034572). It has also been shown to alter the SERPINA1 protein natural conformation thereby contributing to the formation of polymers (PMID: 22735536, 25181470). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 12, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: unknown Allele origin: paternal	Institute of Immunology and Genetics Kaiserslautern Accession: SCV004803203.1 First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024	Comment: ACMG Criteria: PS3, PS4, PM3, PP1_S, PP3, PP5; Individual was compound heterozygous for SERPINA1 variants c.839A>T and c.1096G>A
Pathogenic (Apr 05, 2017)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000740918.3 First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 11778003‚ 18187064 Comment: The p.E366K pathogenic mutation (also known as c.1096G>A), located in coding exon 4 of the SERPINA1 gene, results from a G to A substitution at … (more) The p.E366K pathogenic mutation (also known as c.1096G>A), located in coding exon 4 of the SERPINA1 gene, results from a G to A substitution at nucleotide position 1096. The glutamic acid at codon 366 is replaced by lysine, an amino acid with similar properties. This mutation comprises the common deficiency allele PIZ. The resulting mutant protein polymerizes and aggregates in the endoplasmic reticulum of hepatocytes; in addition, the polymerized protein is resistant to degradation (Carrell RW et al. N. Engl. J. Med., 2002 Jan;346:45-53). Individuals with PIZ/PI*Z have severe alpha-1-antitrypsin (AAT) deficiency with an increased risk for chronic obstructive pulmonary disease; whereas the risk of symptoms due to this mutation in other genotypes is dependent upon the second allele, serum AAT levels, and exposure to environmental risk factors (Köhnlein T et al. Am. J. Med., 2008 Jan;121:3-9; Stoller JK et al. GeneReviews. 2006 Oct 27 [Updated 2017 Jan 19]). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Mar 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198208.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Alpha-1 Antitrypsin Deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000389647.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (22) PubMed: 7045697‚ 3264419‚ 19083091‚ 19738092‚ 2904702‚ 22426792‚ 18340647‚ 3484754‚ 2700304‚ 2339709‚ 6306478‚ 20301692‚ 23632999‚ 21960536‚ 24055113‚ 23858502‚ 25181470‚ 1608473‚ 24328305‚ 22912729‚ 21067581‚ 14522813 Comment: The c.1096G>A (p.Glu366Lys) variant is widely reported in the literature and is also known as p.Glu342Lys, or more commonly, the Z allele. The p.Glu366Lys variant … (more) The c.1096G>A (p.Glu366Lys) variant is widely reported in the literature and is also known as p.Glu342Lys, or more commonly, the Z allele. The p.Glu366Lys variant is the most common deficiency allele accounting for approximately ninety-five percent of clinically recognized cases of alpha-1 antitrypsin deficiency (AATD) (Stoller et al. 2014) and is reported at a frequency of 0.03030 in Utah residents with northern and western European ancestry from the 1000 Genomes Project. This frequency is high but consistent with disease prevalence. The severity of the AATD depends on genotype, with individuals who are homozygous for the p.Glu366Lys variant being at risk of developing both chronic obstructive pulmonary disease (COPD), including emphysema and liver disease. Homozygosity for the variant is a common cause of neonatal cholestasis. The p.Glu366Lys variant rarely leads to AATD-related symptoms in heterozygous individuals (American Thoracic Society 2003; Stoller et al. 2014). Individuals who are homozygous for the p.Glu366Lys variant have approximately 20% of normal circulating alpha-1-antitrypsin levels and individuals who are heterozygous have approximately 61% (Calapoglu et al. 2009; Bornhurst et al. 2013). The decreased serum levels result in decreased functional activity of the AAT protein (Stoller et al. 2014). At least three studies have demonstrated that the low levels of serum AAT are a result of the p.Glu366Lys variant causing an accumulation of the protein in the endoplasmic reticulum of the hepatocyte with subsequent damage to the cells leading to liver disease (Dycaico et al. 1988; Lomas et al. 1992; Hughes et al. 2014). Bartlett et al. (2009) reported that the p.Glu366Lys variant is also a risk factor for liver disease in individuals with cystic fibrosis. Based on the collective evidence, the p.Glu366Lys variant is classified as pathogenic for alpha-1 antitrypsin deficiency. (less)
Pathogenic (Jun 05, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: unknown Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV000840071.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018	Comment: The c.1096G>A (p.Glu366Lys) variant in the SERPINA1 gene is a common pathogenic variant for alpha1-antitrypsin deficiency and is referred to the Z allele [PMID 6306478]. … (more) The c.1096G>A (p.Glu366Lys) variant in the SERPINA1 gene is a common pathogenic variant for alpha1-antitrypsin deficiency and is referred to the Z allele [PMID 6306478]. This variant has been reported in multiple patients with emphysema and liver disease [PMID 23858502, 19083091, 19444872, 26310624, 22912729]. This variant is common in the general population (up to 1.8%). Individual homozygous for this change have severe alpha-1 antitrypsin deficiency and are at risk to develop emphysema: plasma concentrations of alpha1-antitrypsin in homozygous individuals have been reported to be about 22% compared to normal [PMID 19083091]. Individual compound heterozygous for this change and another pathogenic variant (S allele or null allele) have variable alpha-1 antitrypsin deficiency depending on the allele in trans and are at risk to develop emphysema. This variant is classified as pathogenic. <BR>Apparent homozygosity of this variant may be caused by the presence of the mutant allele on both alleles of this individual, or the presence of a mutant allele on one allele and an exonic deletion on the opposite allele. Copy number variant (CNV) analysis or segregation analysis is necessary to assess the apparent homozygosity status of this variant. (less)
Pathogenic (Aug 21, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ALPHA-1-ANTITRYPSIN DEFICIENCY Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV000996188.1 First in ClinVar: Oct 19, 2019 Last updated: Oct 19, 2019	Comment: The c.1096G>A (p.Glu366Lys) variant is widely reported in the literature. It is also referred to as p.Glu342Lys using alternate nomenclature, or is commonly referred to … (more) The c.1096G>A (p.Glu366Lys) variant is widely reported in the literature. It is also referred to as p.Glu342Lys using alternate nomenclature, or is commonly referred to as the Z allele. Individuals homozygous for the p.Glu366Lys variant are at the highest risk for Alpha-1 antitripsin deficiency (AATD) and at risk of developing both chronic obstructive pulmonary disease (COPD), emphysema, liver disease and neonatal cholestasis. The homozygous ZZ allele genotype is a commonly recognized genetic cause of clinically recognized cases of AATD (PMID: 21960536). Individuals homozygous for the p.Glu366Lys variant have approximately 20% of normal circulating alpha-1-antitrypsin levels while individuals who are heterozygous have approximately 61% (PMID: 19083091). It is present in the heterozygous state in the ExAC population database at a frequency of 1.17% (1410/120530) and in the homozygous state in 11 individuals. Based on the available evidence, this variant is classified as pathogenic. (less) Number of individuals with the variant: 1
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Alpha-1-antitrypsin deficiency Affected status: no Allele origin: germline	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill Study: NSIGHT-NC NEXUS Accession: SCV001251536.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020 Comment: carrier finding	Publications: PubMed (2) PubMed: 20301692‚ 15978931 Comment: The SERPINA1 c.1096G>A, (p.E366K) variant (also known as the Z allele) is seen in 1.1% of the human population (gnomAD). It is reported as the … (more) The SERPINA1 c.1096G>A, (p.E366K) variant (also known as the Z allele) is seen in 1.1% of the human population (gnomAD). It is reported as the most common pathogenic allele associated with alpha-1 antitrypsin deficiency (AATD). Individuals homozygous for the Z allele typically have severe AATD (PMID: 15978931). (less) Number of individuals with the variant: 4
Pathogenic (Jan 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: yes Allele origin: germline	DASA Accession: SCV002061259.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022	Publications: PubMed (10) PubMed: 20301692‚ 29644095‚ 29618937‚ 26987331‚ 2904702‚ 19398551‚ 3500183‚ 25966443‚ 29153744‚ 23484243 Comment: The c.1096G>A;p.(Glu366Lys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant ClinVar ID: 17967; PMID: 20301692; 29644095; 29618937; … (more) The c.1096G>A;p.(Glu366Lys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant ClinVar ID: 17967; PMID: 20301692; 29644095; 29618937; 26987331: 20301692) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 2904702, PMID: 19398551; PMID: 3500183) - PS3_supporting. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Serpin domain) - PM1. The p.(Glu366Lys) was detected in trans with a pathogenic variant (PMID: 29882371; 26987331) - PM3_very strong Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. and allele frequency is greater than expected for disorder -BS1. In summary, the currently available evidence indicates that the variant is pathogenic. (less) Number of individuals with the variant: 2 Sex: male Geographic origin: Brazil
Pathogenic (Jan 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alpha-1-antitrypsin deficiency (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV002098344.1 First in ClinVar: Feb 26, 2022 Last updated: Feb 26, 2022	Comment: This individual is homozygous for a well documented variant known as the Z allele that causes a severe form of alpha-1 antitrypsin deficiency. Number of individuals with the variant: 1 Clinical Features: Osteopenia (present) , Orthostatic hypotension (present) , Arthritis (present) , Joint hypermobility (present) , Hemoptysis (present) , Pulmonary embolism (present) , Renal cell carcinoma (present) … (more) Osteopenia (present) , Orthostatic hypotension (present) , Arthritis (present) , Joint hypermobility (present) , Hemoptysis (present) , Pulmonary embolism (present) , Renal cell carcinoma (present) , Vasovagal syncope (present) , Raynaud phenomenon (present) , Graves disease (present) (less) Zygosity: Homozygote Age: 40-49 years Sex: female
Pathogenic (Jan 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502846.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (44) PubMed: 6306478‚ 20981092‚ 24592811‚ 25637381‚ 19738092‚ 23858502‚ 21228398‚ 30739910‚ 19083091‚ 32087139‚ 31028937‚ 24055113‚ 29644095‚ 22426792‚ 30254761‚ 29882371‚ 24082139‚ 26771213‚ 31980526‚ 27246852‚ 25181470‚ 25738741‚ 22735536‚ 31564432‚ 33144682‚ 18340647‚ 22975760‚ 27535533‚ 30068317‚ 29083408‚ 31216405‚ 28146470‚ 27153395‚ 24328305‚ 19444872‚ 27959697‚ 23837941‚ 29431110‚ 26647313‚ 26310624‚ 33726816‚ 30068662‚ 22912729‚ 31447099 Number of individuals with the variant: 4 Secondary finding: no
Pathogenic (Jun 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002568261.1 First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022	Comment: PS3, PS4, PM3, PP3
Pathogenic (Jul 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581126.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS3, PS4, PM3_STR, PP1, PP3	Number of individuals with the variant: 7 Sex: female
Pathogenic (Mar 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV002525833.2 First in ClinVar: Jun 11, 2022 Last updated: Jun 09, 2024	Publications: PMID: 20301692 PMID: 20301692 Number of individuals with the variant: 6
Pathogenic (Mar 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV000328788.3 First in ClinVar: Dec 06, 2016 Last updated: Jun 17, 2024
Pathogenic (Jul 21, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321941.9 First in ClinVar: Oct 09, 2016 Last updated: Sep 16, 2024	Comment: Accounts for 95% of all clinical cases of alpha-1-antitrypsin deficiency (PMID: 25181470); Published functional studies demonstrate that the E366K variant removes a salt bridge to … (more) Accounts for 95% of all clinical cases of alpha-1-antitrypsin deficiency (PMID: 25181470); Published functional studies demonstrate that the E366K variant removes a salt bridge to Lys290 and a hydrogen bond to Thr203, causing misfolding of the protein within the endoplasmic reticulum, which results in a lack of secretion from hepatocytes and a reduction of plasma AAT levels to 10-15% of normal (PMID: 25181470); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; E366K is commonly referred to as the Z variant or E342K by alternative nomenclature; This variant is associated with the following publications: (PMID: 3495177, 23858502, 31216405, 31028937, 24592811, 26771213, 30739910, 30068662, 34828384, 33726816, 35110524, 28146470, 2339709, 1608473, 22426792, 27959697, 29882371, 24055113, 27535533, 27153395, 26310624, 30068317, 29431110, 6306478, 19083091, 22735536, 23837941, 22975760, 25637381, 19444872, 18340647, 19738092, 20981092, 22912729, 24082139, 21228398, 27246852, 25738741, 2700304, 21067581, 29644095, 29083408, 26647313, 24328305, 31564432, 34426522, 25181470, 28121484, 33144682, 35263815, 35433011, 35332129, 32087139, 30254761, 31447099, 31980526, 35786784, 28073160, 32430912, 35753512, 31661293) (less)
Pathogenic (Jul 26, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital Accession: SCV005328427.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024
Pathogenic (Jun 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246283.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: SERPINA1: PS3, PS4, PM5, PP4 Number of individuals with the variant: 51
Pathogenic (Oct 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alpha-1-antitrypsin deficiency (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002767869.3 First in ClinVar: Dec 24, 2022 Last updated: Nov 24, 2024	Publications: PubMed (2) PubMed: 15978931‚ 20301692 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with alpha-1-antitrypsin deficiency (MIM#613490). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0252 - This variant is homozygous. (I) 0305 - Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition (v2: 3124 heterozygotes, 26 homozygotes). (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (7 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Serpin domain (DECIPHER, NCBI conserved domain). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Also known as PI*Z, this is the most common pathogenic allele causing alpha-1-antitrypsin deficiency (ClinVar; PMID: 15978931, 20301692). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Jun 01, 2014)	no assertion criteria provided Method: research	Antitrypsin alpha 1 deficiency (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	CSER _CC_NCGL, University of Washington Study: ESP 6500 variant annotation Accession: SCV000190621.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 Comment: Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
Pathogenic (Jul 29, 2014)	no assertion criteria provided (ACMG Guidelines, 2007) Method: clinical testing	FRAXE (Autosomal recessive inheritance) Affected status: no Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Accession: SCV000223947.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015
other (Jul 15, 2016)	no assertion criteria provided Method: literature only	PI Z Affected status: not provided Allele origin: germline	OMIM Accession: SCV000039864.3 First in ClinVar: Apr 04, 2013 Last updated: Jul 19, 2016	Publications: PubMed (9) PubMed: 2696185‚ 3484754‚ 2989709‚ 3537008‚ 7227484‚ 2904702‚ 18294358‚ 19738092‚ 19398551 Comment on evidence: This is the most frequent allele leading to a high risk of emphysema (and liver disease) in the homozygote; the allele frequency is 0.01-0.02 in … (more) This is the most frequent allele leading to a high risk of emphysema (and liver disease) in the homozygote; the allele frequency is 0.01-0.02 in US Caucasians (Crystal, 1989). Nukiwa et al. (1986) demonstrated the val213-to-ala substitution (here symbolized M1A) in PI*Z in addition to the disease-producing glu342-to-lys mutation. Ala213 was found in all of 40 Z haplotypes, using synthetic oligonucleotide gene probes directed toward the mutated exon 3 sequences in the Z gene. Furthermore, the exon 3 mutation eliminated a BstEII restriction endonuclease site, allowing rapid identification of the change in genomic DNA. Surprisingly, only 23% of the M1 haplotypes were found to be BstEII site negative. The new form of M1, i.e., M1(ala213), is identical to M1 but has an isoelectric focusing 'silent' amino acid substitution. M1 has a frequency of 68 to 76%; M2, 14 to 20%; and M3, 10 to 12%. The Z gene represents 1 to 2% of all alpha-1-antitrypsin haplotypes. Using 2 genomic probes extending into the 5-prime and 3-prime flanking regions, respectively, Cox et al. (1985) identified 8 polymorphic restriction sites for the PI gene. Extensive linkage disequilibrium was found with the PI Z allele throughout the probe region, but not with the normal PI M allele. The Z allele occurred mainly with one haplotype, indicating a single, relatively recent origin in Caucasians. This was an individual who lived in northern Europe some 6,000 years ago. Since then, the variant has spread through Europe with a frequency gradient extending from north to south: 5% of Scandinavians, 4% of Britons, 1 to 2% of southern Europeans, and 3% of the heterogeneous white population in the United States are MZ heterozygotes. Curiously, there is a reciprocal distribution of the S variant form: 10% in southern Europe to 5% in the north. As a general rule then, 1 in 10 persons of European origin will be heterozygous for either the S or Z variant, i.e., MZ or MS (Carrell, 1986). Kawakami et al. (1981) cited 2 studies in which no Pi Z was found among 965 healthy Japanese and 183 Japanese with pulmonary diseases. This is to be compared with a frequency of 1.6% for Pi Z among Norwegians. Crystallographic analysis of alpha-1-antitrypsin predicts that in the normal protein a negatively charged glu342 is adjacent to a positively charged lys290. Thus, the glu342-to-lys Z mutation causes the loss of a normal salt bridge, resulting in intracellular aggregation of the Z molecule. Brantly et al. (1988) predicted that a second mutation that changed the positively charged lys290 to a negatively charged glu290 would correct the secretion defect. They demonstrated that such was the case: when the second mutation was added to the Z-type cDNA, the resulting gene directed the synthesis and secretion of AAT similar to that directed by the normal AAT cDNA in an in vitro eukaryotic expression system. In general it may be possible to correct human hereditary disease by inserting an additional mutation in the gene. By analyzing nonrecombinant SNPs of 21 Latvian and 65 Swedish heterozygous and homozygous PI Z allele carriers and 113 healthy Latvian controls, Lace et al. (2008) estimated the age of the PI Z mutation to be 2,902 years in Latvia and 2,362 years in Sweden. The SNPs showed a high degree of similarity between the 2 populations, indicating a common ancestor. Approximately 3 to 5% of patients with cystic fibrosis (CF; 219700) develop severe liver disease defined as cirrhosis with portal hypertension. Bartlett et al. (2009) performed a 2-stage case control study enrolling patients with CF and severe liver disease with portal hypertension from 63 CF centers in the United States as well as 32 in Canada and 18 outside of North America. In the first stage, 124 patients with CF and severe liver disease, enrolled between January 1999 and December 2004, and 843 control patients without CF-related liver disease (all assessed at greater than 15 years of age) were studied by genotyping 9 polymorphisms in 5 genes previously studied as modifiers of liver disease in CF. In the second stage, the 2 genes that were positive from the first stage were tested in an additional 136 patients with CF-related liver disease enrolled between January 2005 and February 2007, and in 1,088 with no CF-related liver disease. The combined analysis of the initial and replication studies by logistic regression showed CF-related liver disease to be associated with the SERPINA1 Z allele (odds ratio = 5.04; 95% confidence interval 2.88-8.83; p = 1.5 x 10(-8)). Bartlett et al. (2009) concluded that the SERPINA1 Z allele is a risk factor for liver disease in CF. Patients carrying the Z allele are at greater risk (odds ratio = approximately 5) of developing severe liver disease with portal hypertension. Using several markers of ER stress response, Kelly et al. (2009) found that expression of AAT with the Z mutation, which they called ZAAT, resulted in ER stress in transfected HepG2 cells. Coexpression of the ER stress response selenoprotein SEPS1 (607918) relieved ER stress caused by ZAAT expression or by exposure to tunicamycin, a known ER stressor. Supplementation of cells with selenium augmented the activity of SEPS1. Selenium supplementation also increased endogenous SEPS1 expression and reduced ER stress. (less)
Pathogenic (Jun 10, 2016)	no assertion criteria provided Method: research	Alpha-1-antitrypsin deficiency Affected status: unknown Allele origin: germline	Division of Human Genetics, Children's Hospital of Philadelphia Study: CSER-PediSeq Accession: SCV000536708.1 First in ClinVar: Apr 22, 2017 Last updated: Apr 22, 2017	Publications: PubMed (16) PubMed: 6306478‚ 20981092‚ 19738092‚ 23858502‚ 21228398‚ 19083091‚ 24055113‚ 24082139‚ 25181470‚ 22735536‚ 18340647‚ 22975760‚ 24328305‚ 19444872‚ 23837941‚ 22912729
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733412.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (Jan 06, 2020)	no assertion criteria provided Method: curation	Alpha-1-antitrypsin deficiency Affected status: unknown Allele origin: germline	Reproductive Health Research and Development, BGI Genomics Accession: SCV001142445.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020	Comment: NM_000295.4:c.1096G>A (p.Glu366Lys) was reported as p.Glu342Lys, or the Z allele or PIZ. It has an allele frequency of 0.018 in European (no Finnish) subpopulation in … (more) NM_000295.4:c.1096G>A (p.Glu366Lys) was reported as p.Glu342Lys, or the Z allele or PIZ. It has an allele frequency of 0.018 in European (no Finnish) subpopulation in the gnomAD database. Functional studies demonstrate that that this variant plays as an inhibitor of neutrophil elastase and it forms polymers in the lung (PMID: 9569237), and alters the global structural dynamics of alpha-1-Antitrypsin (PMID: 25181470). The Glu342Lys accounts for 95% of all clinical cases of alpha-1-antitrypsin deficiency (PMID: 15978931). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PS4; PP4; PP3; BS1. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001955683.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Uncertain significance (May 13, 2022)	no assertion criteria provided Method: research	Susceptibility to severe coronavirus disease (COVID-19) Affected status: yes Allele origin: germline	HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas Accession: SCV002546356.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022
Pathogenic (Sep 06, 2024)	no assertion criteria provided Method: clinical testing	SERPINA1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004116999.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The SERPINA1 c.1096G>A variant is predicted to result in the amino acid substitution p.Glu366Lys. This variant has been well-documented to be pathogenic for autosomal recessive … (more) The SERPINA1 c.1096G>A variant is predicted to result in the amino acid substitution p.Glu366Lys. This variant has been well-documented to be pathogenic for autosomal recessive alpha-1 antitrypsin deficiency (see for example Table 3 of Dorschner et al. 2013. PubMed ID: 24055113). It is known as the Z allele using legacy nomenclature (GeneReviews, Stoller et al. 1993. PubMed ID: 20301692). We interpret this variant as pathogenic. (less)
other (Dec 01, 1994)	no assertion criteria provided Method: literature only	PI Z(AUGSBURG) Affected status: not provided Allele origin: germline	OMIM Accession: SCV000039892.3 First in ClinVar: Apr 04, 2013 Last updated: Nov 10, 2024	Publications: PubMed (3) PubMed: 3875547‚ 7977369‚ 2575668 Comment on evidence: Using isoelectric focusing with a narrow pH gradient, Weidinger et al. (1985) recognized a rare deficient PI variant, which they called PI Z(Augsburg). To their … (more) Using isoelectric focusing with a narrow pH gradient, Weidinger et al. (1985) recognized a rare deficient PI variant, which they called PI Z(Augsburg). To their surprise, Faber et al. (1990) found that the sequence of the Z(Augsburg) gene showed the common PIZ mutation (M1 glu342 GAG to Z lys342 AAG) which occurred, however, in an M2 ancestral gene. Previous findings indicated that the Z mutation had always been derived from an M1 ala213 background gene. Whitehouse et al. (1989) studied 2 sibs with mild liver abnormality who were found to be compound heterozygotes for the classical PIZ allele and an allele that they called PI*Z(Tun). The Z(Tun) protein appeared to be deficient in the plasma to about the same degree as the Z protein. They found that the mutation was precisely the same as that in the Z allele, namely, a G-to-A transition at codon 342 resulting in the substitution of lysine for glutamic acid; however, the Z(Tun) mutation had occurred on an M2-like haplotype background rather than the M1A background. Because of its association with a unique DNA haplotype and the gene frequency estimates in populations of European origin, the Z mutation is thought to have occurred only once, about 6,000 years ago, in a North European person. The Z gene is very rare among other ethnic groups. (less)
other (Dec 01, 1994)	no assertion criteria provided Method: literature only	PI Z(TUN) Affected status: not provided Allele origin: germline	OMIM Accession: SCV000039893.3 First in ClinVar: Apr 04, 2013 Last updated: Nov 10, 2024	Publications: PubMed (3) PubMed: 3875547‚ 7977369‚ 2575668 Comment on evidence: Using isoelectric focusing with a narrow pH gradient, Weidinger et al. (1985) recognized a rare deficient PI variant, which they called PI Z(Augsburg). To their … (more) Using isoelectric focusing with a narrow pH gradient, Weidinger et al. (1985) recognized a rare deficient PI variant, which they called PI Z(Augsburg). To their surprise, Faber et al. (1990) found that the sequence of the Z(Augsburg) gene showed the common PIZ mutation (M1 glu342 GAG to Z lys342 AAG) which occurred, however, in an M2 ancestral gene. Previous findings indicated that the Z mutation had always been derived from an M1 ala213 background gene. Whitehouse et al. (1989) studied 2 sibs with mild liver abnormality who were found to be compound heterozygotes for the classical PIZ allele and an allele that they called PI*Z(Tun). The Z(Tun) protein appeared to be deficient in the plasma to about the same degree as the Z protein. They found that the mutation was precisely the same as that in the Z allele, namely, a G-to-A transition at codon 342 resulting in the substitution of lysine for glutamic acid; however, the Z(Tun) mutation had occurred on an M2-like haplotype background rather than the M1A background. Because of its association with a unique DNA haplotype and the gene frequency estimates in populations of European origin, the Z mutation is thought to have occurred only once, about 6,000 years ago, in a North European person. The Z gene is very rare among other ethnic groups. (less)
Pathogenic (Dec 08, 2014)	no assertion criteria provided Method: clinical testing	Alpha-1-antitrypsin deficiency Affected status: yes Allele origin: germline	Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital Accession: SCV000608296.1 First in ClinVar: Oct 26, 2017 Last updated: Oct 26, 2017 Comment: Deficiency allele in cis with c.710T>C	Publications: PubMed (1) PubMed: 2989709 Comment: Reduced enzyme activity, 10%-20% of normal Clinical Features: emphysema (present) , COPD (present) , liver disease (present)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001553787.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The SERPINA1 p.E366K variant (referred to as the PIZ allele) is the most common cause of Alpha-1 antitrypsin deficiency (AATD), with 95% of AATD-related disease … (more) The SERPINA1 p.E366K variant (referred to as the PIZ allele) is the most common cause of Alpha-1 antitrypsin deficiency (AATD), with 95% of AATD-related disease reported to be caused by PIZZ (homozygosity for the PIZ allele) (Stoller_2017_PMID:20301692). Homozygosity for the PIZ variant results in decreased plasma concentrations of alpha-1-antitrypsin (~20%) compared to wildtype (CalapoÆ’Ã¼lu_2009_PMID:19083091). The variant was identified in dbSNP (ID: rs28929474) and ClinVar (classified as pathogenic by Illumina, GeneDx, Ambry Genetics, Laboratory for Molecular Medicine, Invitae and 11 other laboratories). The variant was identified in control databases in 3176 of 282742 chromosomes (26 homozygous) at a frequency of 0.01123 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 2369 of 129104 chromosomes (freq: 0.01835), European (Finnish) in 451 of 25112 chromosomes (freq: 0.01796), Other in 71 of 7220 chromosomes (freq: 0.009834), Ashkenazi Jewish in 87 of 10364 chromosomes (freq: 0.008394), Latino in 134 of 35410 chromosomes (freq: 0.003784), African in 62 of 24966 chromosomes (freq: 0.002483) and South Asian in 2 of 30616 chromosomes (freq: 0.000065), but was not observed in the East Asian population. The p.Glu366 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. However, functional studies have demonstrated that the PIZ variant disrupts the native structure of the protein and results in increased polymerization and lack of functional protein (Hughes_2014_PMID:25181470; Lomas_1992_PMID:1608473). In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001927317.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001975439.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (-)	no assertion criteria provided Method: research	Alpha-1-antitrypsin deficiency Affected status: yes Allele origin: unknown	Genomics And Bioinformatics Analysis Resource, Columbia University Accession: SCV004024075.1 First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023 Comment: Homozygous
not provided (-)	no classification provided Method: literature only	Alpha-1-antitrypsin deficiency Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000256612.2 First in ClinVar: Jun 28, 2015 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1519 BookShelf: NBK1519
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Comment:

SERPINA1 c.1096G>A (p.Glu366Lys, commonly known as Z allele or PiMZ) has been associated with increased risk for chronic obstructive pulmonary disease (COPD). This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of European non-Finnish ancestry (1.8%, Genome Aggregation Database (gnomAD); rs28929474) and is present in ClinVar (ID: 17967). Large meta-analyses have reported odds ratios of 2.31-3.54 (OR= 2.31 95% CI [1.60-3.35], Hersh 2004, OR=3.54 95% CI [2.14-5.85] Topic 2012) developing COPD in individuals who are heterozygous for this variant. In vitro functional studies provide some evidence that the p.Glu366Lys variant may impact protein function (Fregonese 2008). In summary, this variant is an established risk factor for COPD. SERPINA1 c.1096G>A (p.Glu366Lys, commonly known as Z allele or PiZZ and historically reported as p.Glu342Lys) has been associated with increased risk for chronic obstructive pulmonary disease (COPD). This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of European non-Finnish ancestry (1.8%, Genome Aggregation Database (gnomAD); rs28929474) and is present in ClinVar (ID: 17967). A large meta-analysis has reported an odds ratio of 42.42 [95% CI 4.41â€“332.55] (Topic 2012) for developing COPD in individuals who are homozygous for this variant. In vitro functional studies provide some evidence that the p.Glu366Lys variant may impact protein function (Fregonese 2008). In summary, this variant is an established risk factor for COPD.

Comment:

NM_000295.4(SERPINA1):c.1096G>A(E366K, aka Z allele) is classified as pathogenic in the context of alpha-1 antitrypsin deficiency. Sources cited for classification include the following: PMID 3264419, 18515255 and 3484754. Classification of NM_000295.4(SERPINA1):c.1096G>A(E366K, aka Z allele) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Comment:

SERPINA1 NM_000295.4 exon 5 p.Glu366Lys (c.1096G>A): This variant, also referred to in the literature as Glu342Lys, is commonly known as the Z allele and is responsible for a large majority of cases of alpha-1-antitrypsin deficiency (A1ATD). It has been reported in the literature in the homozygous state in numerous individuals with severe A1ATD (Brantly 1991 PMID:1889260, Calapoglu 2009 PMID:19083091, Pan 2009 PMID:19444872, Ferrarotti 2012 PMID:22426792, Schaefer 2015 PMID:26310624). In the heterozygous state, it is reported to be a risk factor for COPD, emphysema, and liver disease (Bartlett 2009 PMID:19738092, Ferrarotti 2012 PMID:22426792, Thun 2012 PMID:22912729, Li 2018 PMID:30068317). This variant is also present in 2.1% (1356/64560) of European alleles in the Genome Aggregation Database, including 41 homozygotes (https://gnomad.broadinstitute.org/variant/14-94378610-C-T?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:17967). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown that this variant leads to misfolding and accumulation of protein in hepatocyte endoplasmic reticulum. (Pan 2009 PMID:19444872, Kass 2012 PMID:22735536, Hughes 2013 PMID:25181470). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above.

Comment:

Variant summary: SERPINA1 (formerly known as PI) c.1096G>A (p.Glu366Lys; aka Glu342Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.011 in 251360 control chromosomes, predominantly at a frequency of 0.018 within the European subpopulation in the gnomAD database, including 17 homozygotes. Although the variant reaches polymorphic frequencies in Caucasians, this occurrence is consistent with the disease prevalence (see e.g. Stoller_2005, de Serres_2012, Blanco_2020). The variant, c.1096G>A (commonly known as the Z allele, or PI*Z allele) is reported as the most frequent alpha-1 antitrypsin deficiency allele, and individuals who are homozygous for the variant are at high risk for both lung- and liver disease, reportedly with 80-100% risk for developing emphysema (see e.g. Brantly_1991, Stoller_2005, Bornhorst_2013, Ferrarotti_2012, Stoller_2020, Tejwani_2021, Patel_2021). While nonsmoking heterozygotes are generally not considered to be at significantly increased risk for lung disease, smoking heterozygotes are at increased risk for COPD (Stoller_2020, Tejwani_2021). Several publications reported loss-of-function mechanism for the variant, i.e. homozygous individuals have a serum concentration of alpha-1 antitrypsin (AAT) that is approximately 10%-20% of normal, and the ability of the variant protein to inhibit neutrophil elastase is also decreased (e.g. Ogushi_1987, Bornhorst_2013). In addition, several studies also reported a gain-of-function mechanism for the variant, demonstrating that it can form (toxic) intracellular aggregates, and extracellular polymers with chemotactic properties for neutrophils, resulting in an exacerbated proinflammatory phenotype, especially in response to cigarette smoke (e.g. Elliott_1998, Parmar_2002, Alam_2014). 23 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

SERPINA1 NM_000295.4 exon 5 p.Glu366Lys (c.1096G>A): This variant, also referred to in the literature as Glu342Lys, is commonly known as the Z allele and is responsible for a large majority of cases of alpha-1-antitrypsin deficiency (A1ATD). It has been reported in the literature in the homozygous state in numerous indivdiuals with severe A1ATD (Brantly 1991 PMID:1889260, Calapoglu 2009 PMID:19083091, Pan 2009 PMID:19444872, Ferrarotti 2012 PMID:22426792, Schaefer 2015 PMID:26310624). In the heterozygous state, it is reported to be a risk factor for COPD, emphysema, and liver disease (Bartlett 2009 PMID:19738092, Ferrarotti 2012 PMID:22426792, Thun 2012 PMID:22912729, Li 2018 PMID:30068317). This variant is also present in 2.1% (1356/64560) of European alleles in the Genome Aggregation Database, including 41 homozygotes (https://gnomad.broadinstitute.org/variant/14-94378610-C-T?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:17967). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown that this variant leads to misfolding and accumulation of protein in hepatocyte endoplasmic reticulum. (Pan 2009 PMID:19444872, Kass 2012 PMID:22735536, Hughes 2013 PMID:25181470). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above.

Comment:

The SERPINA1 c.1096G>A (p.Glu366Lys) variant, also known as Gly342Lys or more commonly the Z allele, has been reported in the homozygous and compound heterozygous state in individuals with alpha1-antitrypsin deficiency and is reported as the most common pathogenic variant (Bornhorst JA et al., PMID: 23632999; Calapoğlu et al., PMID: 19083091; Stoller JK et al., PMID: 20301692; Stoller JK and Aboussouan LS, PMID: 21960536). While this variant rarely leads to alpha1-antitrypsin deficiency in heterozygous individuals, individuals that carry this variant in the heterozygous state have an increased risk for developing chronic obstructive pulmonary disease or liver disease (OR: 2.31-7.3; Hersh CP et al., PMID: 15454649; Strnad P et al., PMID: 30068662; Topic A et al., PMID: 22971141). This variant has been reported in the ClinVar database as a germline risk factor or pathogenic variant by many submitters. The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 1.8% in the European (non-Finnish) population which is not inconsistent with the prevalence of alpha1-antitrypsin deficiency (Brode SK et al., PMID: 22761482). The amino acid at this position is critical for protein function (Huang X et al., PMID: 27246852) and computational predictors indicate that the variant is damaging, evidence that correlates with impact to SERPINA1 function. In support of this prediction, functional studies show this variant leads to an accumulation of the protein leading to liver damage, indicating that this variant impacts protein function (Dycaico MJ et al., PMID: 3264419; Lomas DA et al., PMID: 1608473). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 366 of the SERPINA1 protein (p.Glu366Lys). This variant is present in population databases (rs28929474, gnomAD 1.8%), and has an allele count higher than expected for a pathogenic variant. This variant, also referred to as PI*Z allele or Z allele, is a well known cause of severe alpha-1 antitrypsin (AAT) deficiency in the literature (PMID: 15978931, 22426792, 23632999, 1889260). It is associated with an 80%-100% risk of developing emphysema when it is found in the homozygous state, and a 20-50% risk when it is found as a compound heterozygote with the S allele (PMID: 15978931, 22933512). This variant is also known as p.Glu342Lys in the literature. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17967). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SERPINA1 protein function. Experimental studies have shown that this missense change is five times less effective than the normal M allele as an inhibitor of neutrophil elastase and it forms polymers in the lung that can be chemoattractants for neutrophils, thereby increasing inflammation (PMID: 3500183, 9569237, 12034572). It has also been shown to alter the SERPINA1 protein natural conformation thereby contributing to the formation of polymers (PMID: 22735536, 25181470). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.E366K pathogenic mutation (also known as c.1096G>A), located in coding exon 4 of the SERPINA1 gene, results from a G to A substitution at nucleotide position 1096. The glutamic acid at codon 366 is replaced by lysine, an amino acid with similar properties. This mutation comprises the common deficiency allele PI*Z. The resulting mutant protein polymerizes and aggregates in the endoplasmic reticulum of hepatocytes; in addition, the polymerized protein is resistant to degradation (Carrell RW et al. N. Engl. J. Med., 2002 Jan;346:45-53). Individuals with PI*Z/PI*Z have severe alpha-1-antitrypsin (AAT) deficiency with an increased risk for chronic obstructive pulmonary disease; whereas the risk of symptoms due to this mutation in other genotypes is dependent upon the second allele, serum AAT levels, and exposure to environmental risk factors (Köhnlein T et al. Am. J. Med., 2008 Jan;121:3-9; Stoller JK et al. GeneReviews. 2006 Oct 27 [Updated 2017 Jan 19]). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

The c.1096G>A (p.Glu366Lys) variant is widely reported in the literature and is also known as p.Glu342Lys, or more commonly, the Z allele. The p.Glu366Lys variant is the most common deficiency allele accounting for approximately ninety-five percent of clinically recognized cases of alpha-1 antitrypsin deficiency (AATD) (Stoller et al. 2014) and is reported at a frequency of 0.03030 in Utah residents with northern and western European ancestry from the 1000 Genomes Project. This frequency is high but consistent with disease prevalence. The severity of the AATD depends on genotype, with individuals who are homozygous for the p.Glu366Lys variant being at risk of developing both chronic obstructive pulmonary disease (COPD), including emphysema and liver disease. Homozygosity for the variant is a common cause of neonatal cholestasis. The p.Glu366Lys variant rarely leads to AATD-related symptoms in heterozygous individuals (American Thoracic Society 2003; Stoller et al. 2014). Individuals who are homozygous for the p.Glu366Lys variant have approximately 20% of normal circulating alpha-1-antitrypsin levels and individuals who are heterozygous have approximately 61% (Calapoglu et al. 2009; Bornhurst et al. 2013). The decreased serum levels result in decreased functional activity of the AAT protein (Stoller et al. 2014). At least three studies have demonstrated that the low levels of serum AAT are a result of the p.Glu366Lys variant causing an accumulation of the protein in the endoplasmic reticulum of the hepatocyte with subsequent damage to the cells leading to liver disease (Dycaico et al. 1988; Lomas et al. 1992; Hughes et al. 2014). Bartlett et al. (2009) reported that the p.Glu366Lys variant is also a risk factor for liver disease in individuals with cystic fibrosis. Based on the collective evidence, the p.Glu366Lys variant is classified as pathogenic for alpha-1 antitrypsin deficiency.

Comment:

The c.1096G>A (p.Glu366Lys) variant in the SERPINA1 gene is a common pathogenic variant for alpha1-antitrypsin deficiency and is referred to the Z allele [PMID 6306478]. This variant has been reported in multiple patients with emphysema and liver disease [PMID 23858502, 19083091, 19444872, 26310624, 22912729]. This variant is common in the general population (up to 1.8%). Individual homozygous for this change have severe alpha-1 antitrypsin deficiency and are at risk to develop emphysema: plasma concentrations of alpha1-antitrypsin in homozygous individuals have been reported to be about 22% compared to normal [PMID 19083091]. Individual compound heterozygous for this change and another pathogenic variant (S allele or null allele) have variable alpha-1 antitrypsin deficiency depending on the allele in trans and are at risk to develop emphysema. This variant is classified as pathogenic. <BR>Apparent homozygosity of this variant may be caused by the presence of the mutant allele on both alleles of this individual, or the presence of a mutant allele on one allele and an exonic deletion on the opposite allele. Copy number variant (CNV) analysis or segregation analysis is necessary to assess the apparent homozygosity status of this variant.

Comment:

The c.1096G>A (p.Glu366Lys) variant is widely reported in the literature. It is also referred to as p.Glu342Lys using alternate nomenclature, or is commonly referred to as the Z allele. Individuals homozygous for the p.Glu366Lys variant are at the highest risk for Alpha-1 antitripsin deficiency (AATD) and at risk of developing both chronic obstructive pulmonary disease (COPD), emphysema, liver disease and neonatal cholestasis. The homozygous ZZ allele genotype is a commonly recognized genetic cause of clinically recognized cases of AATD (PMID: 21960536). Individuals homozygous for the p.Glu366Lys variant have approximately 20% of normal circulating alpha-1-antitrypsin levels while individuals who are heterozygous have approximately 61% (PMID: 19083091). It is present in the heterozygous state in the ExAC population database at a frequency of 1.17% (1410/120530) and in the homozygous state in 11 individuals. Based on the available evidence, this variant is classified as pathogenic.

Comment:

The SERPINA1 c.1096G>A, (p.E366K) variant (also known as the Z allele) is seen in 1.1% of the human population (gnomAD). It is reported as the most common pathogenic allele associated with alpha-1 antitrypsin deficiency (AATD). Individuals homozygous for the Z allele typically have severe AATD (PMID: 15978931).

Comment:

The c.1096G>A;p.(Glu366Lys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant ClinVar ID: 17967; PMID: 20301692; 29644095; 29618937; 26987331: 20301692) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 2904702, PMID: 19398551; PMID: 3500183) - PS3_supporting. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Serpin domain) - PM1. The p.(Glu366Lys) was detected in trans with a pathogenic variant (PMID: 29882371; 26987331) - PM3_very strong Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. and allele frequency is greater than expected for disorder -BS1. In summary, the currently available evidence indicates that the variant is pathogenic.

Comment:

Accounts for 95% of all clinical cases of alpha-1-antitrypsin deficiency (PMID: 25181470); Published functional studies demonstrate that the E366K variant removes a salt bridge to Lys290 and a hydrogen bond to Thr203, causing misfolding of the protein within the endoplasmic reticulum, which results in a lack of secretion from hepatocytes and a reduction of plasma AAT levels to 10-15% of normal (PMID: 25181470); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; E366K is commonly referred to as the Z variant or E342K by alternative nomenclature; This variant is associated with the following publications: (PMID: 3495177, 23858502, 31216405, 31028937, 24592811, 26771213, 30739910, 30068662, 34828384, 33726816, 35110524, 28146470, 2339709, 1608473, 22426792, 27959697, 29882371, 24055113, 27535533, 27153395, 26310624, 30068317, 29431110, 6306478, 19083091, 22735536, 23837941, 22975760, 25637381, 19444872, 18340647, 19738092, 20981092, 22912729, 24082139, 21228398, 27246852, 25738741, 2700304, 21067581, 29644095, 29083408, 26647313, 24328305, 31564432, 34426522, 25181470, 28121484, 33144682, 35263815, 35433011, 35332129, 32087139, 30254761, 31447099, 31980526, 35786784, 28073160, 32430912, 35753512, 31661293)

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with alpha-1-antitrypsin deficiency (MIM#613490). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0252 - This variant is homozygous. (I) 0305 - Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition (v2: 3124 heterozygotes, 26 homozygotes). (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (7 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Serpin domain (DECIPHER, NCBI conserved domain). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Also known as PI*Z, this is the most common pathogenic allele causing alpha-1-antitrypsin deficiency (ClinVar; PMID: 15978931, 20301692). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

NM_000295.4:c.1096G>A (p.Glu366Lys) was reported as p.Glu342Lys, or the Z allele or PI*Z. It has an allele frequency of 0.018 in European (no Finnish) subpopulation in the gnomAD database. Functional studies demonstrate that that this variant plays as an inhibitor of neutrophil elastase and it forms polymers in the lung (PMID: 9569237), and alters the global structural dynamics of alpha-1-Antitrypsin (PMID: 25181470). The Glu342Lys accounts for 95% of all clinical cases of alpha-1-antitrypsin deficiency (PMID: 15978931). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PS4; PP4; PP3; BS1.

Comment:

The SERPINA1 c.1096G>A variant is predicted to result in the amino acid substitution p.Glu366Lys. This variant has been well-documented to be pathogenic for autosomal recessive alpha-1 antitrypsin deficiency (see for example Table 3 of Dorschner et al. 2013. PubMed ID: 24055113). It is known as the Z allele using legacy nomenclature (GeneReviews, Stoller et al. 1993. PubMed ID: 20301692). We interpret this variant as pathogenic.

Comment:

The SERPINA1 p.E366K variant (referred to as the PI*Z allele) is the most common cause of Alpha-1 antitrypsin deficiency (AATD), with 95% of AATD-related disease reported to be caused by PI*ZZ (homozygosity for the PI*Z allele) (Stoller_2017_PMID:20301692). Homozygosity for the PI*Z variant results in decreased plasma concentrations of alpha-1-antitrypsin (~20%) compared to wildtype (CalapoÆ’Ã¼lu_2009_PMID:19083091). The variant was identified in dbSNP (ID: rs28929474) and ClinVar (classified as pathogenic by Illumina, GeneDx, Ambry Genetics, Laboratory for Molecular Medicine, Invitae and 11 other laboratories). The variant was identified in control databases in 3176 of 282742 chromosomes (26 homozygous) at a frequency of 0.01123 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 2369 of 129104 chromosomes (freq: 0.01835), European (Finnish) in 451 of 25112 chromosomes (freq: 0.01796), Other in 71 of 7220 chromosomes (freq: 0.009834), Ashkenazi Jewish in 87 of 10364 chromosomes (freq: 0.008394), Latino in 134 of 35410 chromosomes (freq: 0.003784), African in 62 of 24966 chromosomes (freq: 0.002483) and South Asian in 2 of 30616 chromosomes (freq: 0.000065), but was not observed in the East Asian population. The p.Glu366 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. However, functional studies have demonstrated that the PI*Z variant disrupts the native structure of the protein and results in increased polymerization and lack of functional protein (Hughes_2014_PMID:25181470; Lomas_1992_PMID:1608473). In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
effect on catalytic protein function (VariO:0008)			Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital Accession: SCV000608296.1	Publications PubMed (1)

Comment:

SERPINA1 NM_000295.4 exon 5 p.Glu366Lys (c.1096G>A): This variant, also referred to in the literature as Glu342Lys, is commonly known as the Z allele and is responsible for a large majority of cases of alpha-1-antitrypsin deficiency (A1ATD). It has been reported in the literature in the homozygous state in numerous indivdiuals with severe A1ATD (Brantly 1991 PMID:1889260, Calapoglu 2009 PMID:19083091, Pan 2009 PMID:19444872, Ferrarotti 2012 PMID:22426792, Schaefer 2015 PMID:26310624). In the heterozygous state, it is reported to be a risk factor for COPD, emphysema, and liver disease (Bartlett 2009 PMID:19738092, Ferrarotti 2012 PMID:22426792, Thun 2012 PMID:22912729, Li 2018 PMID:30068317). This variant is also present in 2.1% (1356/64560) of European alleles in the Genome Aggregation Database, including 41 homozygotes (https://gnomad.broadinstitute.org/variant/14-94378610-C-T?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:17967). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown that this variant leads to misfolding and accumulation of protein in hepatocyte endoplasmic reticulum. (Pan 2009 PMID:19444872, Kass 2012 PMID:22735536, Hughes 2013 PMID:25181470). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Alpha-1 Antitrypsin Deficiency.	Adam MP	-	2023	PMID: 20301692
The spectrum of clinical sequelae associated with alpha-1 antitrypsin deficiency.	Tejwani V	Therapeutic advances in chronic disease	2021	PMID: 34408829
Liver disease with unknown etiology - have you ruled out alpha-1 antitrypsin deficiency?	Patel D	Therapeutic advances in chronic disease	2021	PMID: 34408828
Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients.	Stranneheim H	Genome medicine	2021	PMID: 33726816
Impact of integrated translational research on clinical exome sequencing.	Klee EW	Genetics in medicine : official journal of the American College of Medical Genetics	2021	PMID: 33144682
Prevalence of α(1)-antitrypsin PiZZ genotypes in patients with COPD in Europe: a systematic review.	Blanco I	European respiratory review : an official journal of the European Respiratory Society	2020	PMID: 32699024
Null(Canada): A novel α(1)-antitrypsin allele with in cis variants Glu366Lys and Ile100Asn.	Chen S	Clinical biochemistry	2020	PMID: 32087139
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.	Hou YC	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31980526
A Randomized, Controlled Trial of the Analytic and Diagnostic Performance of Singleton and Trio, Rapid Genome and Exome Sequencing in Ill Infants.	Kingsmore SF	American journal of human genetics	2019	PMID: 31564432
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.	eMERGE Consortium. Electronic address: [email protected]	American journal of human genetics	2019	PMID: 31447099
Reanalysis of Clinical Exome Sequencing Data.	Liu P	The New England journal of medicine	2019	PMID: 31216405
Development of a Novel Next-Generation Sequencing Assay for Carrier Screening in Old Order Amish and Mennonite Populations of Pennsylvania.	Crowgey EL	The Journal of molecular diagnostics : JMD	2019	PMID: 31028937
SERPINA1 Z allele is associated with cystic fibrosis liver disease.	Boëlle PY	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30739910
Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.	Strnad P	Gut	2019	PMID: 30068662
Sequencing Alpha-1 MZ Individuals Shows Frequent Biallelic Mutations.	Foil KE	Pulmonary medicine	2018	PMID: 30254761
Genome-wide association study of lung function and clinical implication in heavy smokers.	Li X	BMC medical genetics	2018	PMID: 30068317
Real-world clinical applicability of pathogenicity predictors assessed on SERPINA1 mutations in alpha-1-antitrypsin deficiency.	Giacopuzzi E	Human mutation	2018	PMID: 29882371
Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization.	Farnaes L	NPJ genomic medicine	2018	PMID: 29644095
The impact of alpha-1 antitrypsin augmentation therapy on neutrophil-driven respiratory disease in deficient individuals.	Dunlea DM	Journal of inflammation research	2018	PMID: 29618937
The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants.	Reuter MS	CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne	2018	PMID: 29431110
Molecular and functional characterization of familial chylomicronemia syndrome.	Teramoto R	Atherosclerosis	2018	PMID: 29153744
Exome-wide association study of plasma lipids in >300,000 individuals.	Liu DJ	Nature genetics	2017	PMID: 29083408
Rare and low-frequency coding variants alter human adult height.	Marouli E	Nature	2017	PMID: 28146470
Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation.	Posey JE	The New England journal of medicine	2017	PMID: 27959697
Analysis of protein-coding genetic variation in 60,706 humans.	Lek M	Nature	2016	PMID: 27535533
Molecular Mechanism of Z α1-Antitrypsin Deficiency.	Huang X	The Journal of biological chemistry	2016	PMID: 27246852
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.	Maxwell KN	American journal of human genetics	2016	PMID: 27153395
Frequency of Rare Alpha-1 Antitrypsin Variants in Polish Patients with Chronic Respiratory Disorders.	Duk K	Advances in experimental medicine and biology	2016	PMID: 26987331
A study of common Mendelian disease carriers across ageing British cohorts: meta-analyses reveal heterozygosity for alpha 1-antitrypsin deficiency increases respiratory capacity and height.	North TL	Journal of medical genetics	2016	PMID: 26831755
Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease.	Hobbs BD	American journal of respiratory and critical care medicine	2016	PMID: 26771213
Aberrant disulphide bonding contributes to the ER retention of alpha1-antitrypsin deficiency variants.	Ronzoni R	Human molecular genetics	2016	PMID: 26647313
Prevalence of PIZ and PIS alleles of alpha-1-antitrypsin deficiency in Finland.	Häggblom J	European clinical respiratory journal	2015	PMID: 26672964
Impaired hepcidin expression in alpha-1-antitrypsin deficiency associated with iron overload and progressive liver disease.	Schaefer B	Human molecular genetics	2015	PMID: 26310624
Fibrinogen and α1-antitrypsin in COPD exacerbations.	Ingebrigtsen TS	Thorax	2015	PMID: 26304913
Quantitation of circulating wild-type alpha-1-antitrypsin in heterozygous carriers of the S and Z deficiency alleles.	Donato LJ	Respiratory research	2015	PMID: 26243289
Spectrum of mutations of the LPL gene identified in Italy in patients with severe hypertriglyceridemia.	Rabacchi C	Atherosclerosis	2015	PMID: 25966443
An antibody raised against a pathogenic serpin variant induces mutant-like behaviour in the wild-type protein.	Irving JA	The Biochemical journal	2015	PMID: 25738741
Actionable exomic incidental findings in 6503 participants: challenges of variant classification.	Amendola LM	Genome research	2015	PMID: 25637381
The Z mutation alters the global structural dynamics of α1-antitrypsin.	Hughes VA	PloS one	2014	PMID: 25181470
Z α1-antitrypsin confers a proinflammatory phenotype that contributes to chronic obstructive pulmonary disease.	Alam S	American journal of respiratory and critical care medicine	2014	PMID: 24592811
Pi*Z heterozygous alpha-1 antitrypsin states accelerate parenchymal but not biliary cirrhosis.	Cacciottolo TM	European journal of gastroenterology & hepatology	2014	PMID: 24518491
Clarification of the risk of chronic obstructive pulmonary disease in α1-antitrypsin deficiency PiMZ heterozygotes.	Molloy K	American journal of respiratory and critical care medicine	2014	PMID: 24428606
Increased outer arm and core fucose residues on the N-glycans of mutated alpha-1 antitrypsin protein from alpha-1 antitrypsin deficient individuals.	McCarthy C	Journal of proteome research	2014	PMID: 24328305
Extensive sequence analysis of CFTR, SCNN1A, SCNN1B, SCNN1G and SERPINA1 suggests an oligogenic basis for cystic fibrosis-like phenotypes.	Ramos MD	Clinical genetics	2014	PMID: 23837941
Personalized genomic disease risk of volunteers.	Gonzalez-Garay ML	Proceedings of the National Academy of Sciences of the United States of America	2013	PMID: 24082139
Actionable, pathogenic incidental findings in 1,000 participants' exomes.	Dorschner MO	American journal of human genetics	2013	PMID: 24055113
A patient with the rare alpha-1-antitrypsin variant (Z)bristol in compound heterozygosity with the Z mutation.	Bates KJ	Annals of clinical biochemistry	2013	PMID: 23858502
α1-Antitrypsin phenotypes and associated serum protein concentrations in a large clinical population.	Bornhorst JA	Chest	2013	PMID: 23632999
Severe hypertriglyceridemia in an infant of Arab descent.	Behar DM	The Israel Medical Association journal : IMAJ	2013	PMID: 23484243
An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals.	Lazarin GA	Genetics in medicine : official journal of the American College of Medical Genetics	2013	PMID: 22975760
Alpha-1-antitrypsin deficiency in Serbian adults with lung diseases.	Topic A	Genetic testing and molecular biomarkers	2012	PMID: 22971141
Prevalence of α1-antitrypsin deficiency alleles PIS and PIZ worldwide and effective screening for each of the five phenotypic classes PIMS, PIMZ, PISS, PISZ, and PI*ZZ: a comprehensive review.	de Serres FJ	Therapeutic advances in respiratory disease	2012	PMID: 22933512
SERPINA1 PiZ and PiS heterozygotes and lung function decline in the SAPALDIA cohort.	Thun GA	PloS one	2012	PMID: 22912729
Conformational properties of the disease-causing Z variant of α1-antitrypsin revealed by theory and experiment.	Kass I	Biophysical journal	2012	PMID: 22735536
Serum levels and genotype distribution of α1-antitrypsin in the general population.	Ferrarotti I	Thorax	2012	PMID: 22426792
A review of α1-antitrypsin deficiency.	Stoller JK	American journal of respiratory and critical care medicine	2012	PMID: 21960536
Carrier testing for severe childhood recessive diseases by next-generation sequencing.	Bell CJ	Science translational medicine	2011	PMID: 21228398
Alpha-1 antitrypsin gene polymorphism in Chronic Obstructive Pulmonary Disease (COPD).	Denden S	Genetics and molecular biology	2010	PMID: 21637600
Polymorphism of SERPINE2 gene is associated with pulmonary emphysema in consecutive autopsy cases.	Fujimoto K	BMC medical genetics	2010	PMID: 21067581
A map of human genome variation from population-scale sequencing.	1000 Genomes Project Consortium	Nature	2010	PMID: 20981092
Genetic modifiers of liver disease in cystic fibrosis.	Bartlett JR	JAMA	2009	PMID: 19738092
Single nucleotide polymorphism-mediated translational suppression of endoplasmic reticulum mannosidase I modifies the onset of end-stage liver disease in alpha1-antitrypsin deficiency.	Pan S	Hepatology (Baltimore, Md.)	2009	PMID: 19444872
Selenoprotein S/SEPS1 modifies endoplasmic reticulum stress in Z variant alpha1-antitrypsin deficiency.	Kelly E	The Journal of biological chemistry	2009	PMID: 19398551
Analysis of the alpha-1-antitrypsin deficient alleles M3S, MZ, and ZZ by biochemical and molecular methods: a family study.	Calapoğlu M	Biochemical genetics	2009	PMID: 19083091
SERPINA1 gene variants in individuals from the general population with reduced alpha1-antitrypsin concentrations.	Zorzetto M	Clinical chemistry	2008	PMID: 18515255
Population-based case-control study of alpha 1-antitrypsin and SLC11A1 in Crohn's disease and ulcerative colitis.	Kotlowski R	Inflammatory bowel diseases	2008	PMID: 18340647
Age of SERPINA1 gene PI Z mutation: Swedish and Latvian population analysis.	Lace B	Annals of human genetics	2008	PMID: 18294358
Alpha-1 antitrypsin deficiency: pathogenesis, clinical presentation, diagnosis, and treatment.	Köhnlein T	The American journal of medicine	2008	PMID: 18187064
Laboratory diagnosis of alpha1-antitrypsin deficiency.	Ferrarotti I	Translational research : the journal of laboratory and clinical medicine	2007	PMID: 17964515
Alpha1-antitrypsin deficiency.	Stoller JK	Lancet (London, England)	2005	PMID: 15978931
Chronic obstructive pulmonary disease in alpha1-antitrypsin PI MZ heterozygotes: a meta-analysis.	Hersh CP	Thorax	2004	PMID: 15454649
American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency.	American Thoracic Society	American journal of respiratory and critical care medicine	2003	PMID: 14522813
Polymers of alpha(1)-antitrypsin are chemotactic for human neutrophils: a new paradigm for the pathogenesis of emphysema.	Parmar JS	American journal of respiratory cell and molecular biology	2002	PMID: 12034572
Alpha1-antitrypsin deficiency--a model for conformational diseases.	Carrell RW	The New England journal of medicine	2002	PMID: 11778003
Lung polymers in Z alpha1-antitrypsin deficiency-related emphysema.	Elliott PR	American journal of respiratory cell and molecular biology	1998	PMID: 9569237
Review: alpha 1-antitrypsin deficiency associated liver disease.	Qu D	Journal of gastroenterology and hepatology	1997	PMID: 9195389
Clinical features of individuals with PI*SZ phenotype of alpha 1-antitrypsin deficiency. alpha 1-Antitrypsin Deficiency Registry Study Group.	Turino GM	American journal of respiratory and critical care medicine	1996	PMID: 8970361
Identification and DNA sequence analysis of 15 new alpha 1-antitrypsin variants, including two PIQ0 alleles and one deficient PIM allele.	Faber JP	American journal of human genetics	1994	PMID: 7977369
The mechanism of Z alpha 1-antitrypsin accumulation in the liver.	Lomas DA	Nature	1992	PMID: 1608473
Use of a highly purified alpha 1-antitrypsin standard to establish ranges for the common normal and deficient alpha 1-antitrypsin phenotypes.	Brantly ML	Chest	1991	PMID: 1889260
Sequence data of the rare deficient alpha 1-antitrypsin variant PI Zaugsburg.	Faber JP	American journal of human genetics	1990	PMID: 2339709
Alpha-1-antitrypsin deficiency: accumulation or degradation of mutant variants within the hepatic endoplasmic reticulum.	Sifers RN	American journal of respiratory cell and molecular biology	1989	PMID: 2700304
The alpha 1-antitrypsin gene and its deficiency states.	Crystal RG	Trends in genetics : TIG	1989	PMID: 2696185
Genetic studies on a new deficiency gene (PI*Ztun) at the PI locus.	Whitehouse DB	Journal of medical genetics	1989	PMID: 2575668
Neonatal hepatitis induced by alpha 1-antitrypsin: a transgenic mouse model.	Dycaico MJ	Science (New York, N.Y.)	1988	PMID: 3264419
Repair of the secretion defect in the Z form of alpha 1-antitrypsin by addition of a second mutation.	Brantly M	Science (New York, N.Y.)	1988	PMID: 2904702
Z-type alpha 1-antitrypsin is less competent than M1-type alpha 1-antitrypsin as an inhibitor of neutrophil elastase.	Ogushi F	The Journal of clinical investigation	1987	PMID: 3500183
alpha 1-Antitrypsin: molecular pathology, leukocytes, and tissue damage.	Carrell RW	The Journal of clinical investigation	1986	PMID: 3537008
Evaluation of "at risk" alpha 1-antitrypsin genotype SZ with synthetic oligonucleotide gene probes.	Nukiwa T	The Journal of clinical investigation	1986	PMID: 3484754
Alpha-1-antitrypsin: evidence for a fifth PI M subtype and a new deficiency allele PI*Z augsburg.	Weidinger S	Human genetics	1985	PMID: 3875547
DNA restriction fragments associated with alpha 1-antitrypsin indicate a single origin for deficiency allele PI Z.	Cox DW	Nature	1985	PMID: 2989709
alpha 1-antitrypsin deficiency detection by direct analysis of the mutation in the gene.	Kidd VJ	Nature	1983	PMID: 6306478
Structure and variation of human alpha 1-antitrypsin.	Carrell RW	Nature	1982	PMID: 7045697
Familial aggregation of abnormal ventilatory control and pulmonary function in chronic obstructive pulmonary disease.	Kawakami Y	European journal of respiratory diseases	1981	PMID: 7227484
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SERPINA1	-	-	-	-
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Text-mined citations for rs28929474 ...

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Record last updated Dec 15, 2024

ClinVar Genomic variation as it relates to human health

NM_001127701.1(SERPINA1):c.1096G>A (p.Glu366Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28929474 ...