VCV000003632.55 - ClinVar

NM_000250.2(MPO):c.2031-2A>C

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.

(21)

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.

Conflicting classifications of pathogenicity
Pathogenic(6); Likely pathogenic(5); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of a Genotype

NM_000250.2(MPO):c.[2031-2A>C];[752T>C]

Identifiers

NM_000250.2(MPO):c.2031-2A>C

Variation ID: 3632 Accession: VCV000003632.55

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q22 17: 58270865 (GRCh38) [ NCBI UCSC ] 17: 56348226 (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	Jul 5, 2015	Nov 24, 2024	Nov 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000250.2:c.2031-2A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NC_000017.11:g.58270865T>G
NC_000017.10:g.56348226T>G
NG_009629.1:g.15071A>C
LRG_84:g.15071A>C
LRG_84t1:c.2031-2A>C

... more HGVS ... less HGVS

Protein change

Other names

IVS11AS, A-C, -2

Canonical SPDI

NC_000017.11:58270864:T:G

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

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.

0.00080 (G)

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

1000 Genomes Project 30x 0.00062

1000 Genomes Project 0.00080

Trans-Omics for Precision Medicine (TOPMed) 0.00400

Exome Aggregation Consortium (ExAC) 0.00426

The Genome Aggregation Database (gnomAD), exomes 0.00437

The Genome Aggregation Database (gnomAD) 0.00472

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00523

Links

ClinGen: CA212810 OMIM: 606989.0007 dbSNP: rs35897051 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.
LPO		-	-	GRCh38 GRCh37	47	64
MPO		-	-	GRCh38 GRCh37	45	111

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.
Myeloperoxidase deficiency	Pathogenic/Likely pathogenic (11)	criteria provided, multiple submitters, no conflicts	Mar 26, 2024	RCV000003816.30
not provided	Pathogenic/Likely pathogenic (7)	criteria provided, multiple submitters, no conflicts	Nov 16, 2024	RCV000265536.41
Alzheimer disease type 1 Myeloperoxidase deficiency	Pathogenic (1)	criteria provided, single submitter	Apr 12, 2022	RCV002482823.8
MPO-related disorder	Pathogenic (1)	no assertion criteria provided	Sep 5, 2024	RCV003398437.6
not specified	Uncertain significance (1)	criteria provided, single submitter	May 1, 2024	RCV004689407.1

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 (Sep 26, 2014)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Myeloperoxidase deficiency (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Study: CSER-MedSeq Accession: SCV000221199.2 First in ClinVar: Apr 01, 2015 Last updated: Jul 05, 2015	Publications: PubMed (3) PubMed: 15108282‚ 9766845‚ 6260268 Comment: The 2031-2A>C variant in MPO has been previously identified in 1 compound heterozygous and 2 homozygous individuals with myeloperoxidase deficiency (Marchetti 2004). This variant is … (more) The 2031-2A>C variant in MPO has been previously identified in 1 compound heterozygous and 2 homozygous individuals with myeloperoxidase deficiency (Marchetti 2004). This variant is located in the 3' splice region and functional studies indicate that this variant leads to altered splicing (Marchetti 2004). In summary, the 2031-2A>C variant meets our criteria to be considered causative for myeloperoxidase deficiency (MPOD) in a recessive manner. However, the clinical relevance of MPOD is not well-established. (less) Number of individuals with the variant: 2
Likely pathogenic (Jul 08, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myeloperoxidase deficiency Affected status: unknown Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Accession: SCV001448821.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 1 Clinical Features: Seizures (present) , Language impairment (present) , Speech articulation difficulties (present) , Global developmental delay (present) , Abnormality of the optic nerve (present) , Delayed … (more) Seizures (present) , Language impairment (present) , Speech articulation difficulties (present) , Global developmental delay (present) , Abnormality of the optic nerve (present) , Delayed speech and language development (present) , Short stature (present) , Chronic diarrhea (present) , Dolichocephaly (present) , Deeply set eye (present) , Frontal bossing (present) , Generalized hypotonia (present) , Small for gestational age (present) , Recurrent hypoglycemia (present) , Episodic fever (present) , Lactic acidosis (present) , Chronic neutropenia (present) , Motor aphasia (present) , Recurrent bacterial skin infections (present) (less) Sex: male
Likely pathogenic (Mar 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502221.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (9) PubMed: 15108282‚ 26764160‚ 32531373‚ 32758447‚ 31980526‚ 34426522‚ 26822949‚ 30487145‚ 32758448 Number of individuals with the variant: 3 Secondary finding: no
Pathogenic (Apr 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alzheimer disease type 1 Myeloperoxidase deficiency Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002778311.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002009349.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Likely pathogenic (Nov 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myeloperoxidase deficiency Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002023510.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myeloperoxidase deficiency Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004806673.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Likely pathogenic (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myeloperoxidase deficiency Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001439966.1 First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020	Comment: This variant was identified as compound heterozygous.
Pathogenic (Mar 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myeloperoxidase deficiency Affected status: unknown Allele origin: germline	Payam Genetics Center, General Welfare Department of North Khorasan Province Accession: SCV003924023.1 First in ClinVar: May 13, 2023 Last updated: May 13, 2023	Number of individuals with the variant: 1 Age: 0-9 years Sex: male Ethnicity/Population group: Iranian Geographic origin: Iran
Uncertain significance (May 01, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005184390.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024	Publications: PubMed (2) PubMed: 32758447‚ 15108282 Comment: Variant summary: MPO c.2031-2A>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more) Variant summary: MPO c.2031-2A>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing , and the predominant products were truncated MPO (Haskamp_2020), such mRNA products are not subject to NMD. The variant allele was found at a frequency of 0.0044 in 251174 control chromosomes in the gnomAD database, including 2 homozygotes (gnomAD v2), and in gnomAD v4 dataset, this vairant was found a frequency of 0.0066 in 1179978 control chromosomes in European (non-Finnish) group with 25 homozygotes, suggesting that the variant may be benign. c.2031-2A>C has been reported in the literature in at-least three individuals affected with Myeloperoxidase Deficiency (example, Marchetti_2004). Additionally, no pathogenic missense or in-frame changes from the last exon have been reported in ClinVar, suggesting the disrupted last exon may not be functionally important. The following publications have been ascertained in the context of this evaluation (PMID: 32758447, 15108282). ClinVar contains an entry for this variant (Variation ID: 3632). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Likely pathogenic (Jan 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: SCV001334657.25 First in ClinVar: Jun 08, 2020 Last updated: Oct 20, 2024	Comment: MPO: PM3, PS3:Moderate, PM2:Supporting, PP3 Number of individuals with the variant: 7
Pathogenic (Nov 16, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329427.11 First in ClinVar: Dec 06, 2016 Last updated: Nov 24, 2024	Comment: Reported as a heterozygous germline variant in multiple individuals with myeloid neoplasms (PMID: 35761024); Splice site variant that destroys the canonical splice acceptor site in … (more) Reported as a heterozygous germline variant in multiple individuals with myeloid neoplasms (PMID: 35761024); Splice site variant that destroys the canonical splice acceptor site in intron 11, and causes the activation of a cryptic splice site located 109 nucleotides upstream of the authentic splice site (PMID: 15108282); This variant is associated with the following publications: (PMID: 20974672, 25714468, 34662886, 35026467, 24385801, 17384005, 15108282, 26764160, 26822949, 27301573, 27827828, 30487145, 31980526, 32758448, 34426522, 32531373, 35761024, 36730508, 37868038, 38170104, 32758447) (less)
Pathogenic (May 01, 2004)	no assertion criteria provided Method: literature only	MYELOPEROXIDASE DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023981.4 First in ClinVar: Apr 04, 2013 Last updated: Dec 19, 2020	Publications: PubMed (1) PubMed: 15108282 Comment on evidence: In 2 female Italian patients (patients 1 and 7) with complete myeloperoxidase deficiency (MPOD; 254600), Marchetti et al. (2004) identified homozygosity for a 2031A-C transversion … (more) In 2 female Italian patients (patients 1 and 7) with complete myeloperoxidase deficiency (MPOD; 254600), Marchetti et al. (2004) identified homozygosity for a 2031A-C transversion in the 3-prime splice site of intron 11 of the MPO gene (IVS11AS-2A-C). In a third patient (patient 13) with complete MPOD, they identified the IVS11AS-2A-C transversion in compound heterozygous state with a 14-bp deletion in exon 9 of the MPO gene (606989.0004). Because of difficulty in obtaining bone marrow samples from MPO-deficient patients to study MPO mRNA splicing in vivo, the authors set up a eukaryotic expression system to investigate how the IVS11AS-2-A-C mutation alters MPO pre-mRNA splicing. Activation of a cryptic 3-prime splice site located 109 bp upstream of the authentic 3-prime splice site was observed. The 109-bp insertion caused a frameshift, resulting in a premature stop codon and an abnormal MPO precursor lacking enzymatic activity. (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: SCV001957582.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 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: SCV001971230.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (May 22, 2023)	no assertion criteria provided Method: clinical testing	Myeloperoxidase deficiency Affected status: yes Allele origin: maternal	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV004242199.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Number of individuals with the variant: 1 Clinical Features: Recurrent urinary tract infections (present) , Neurogenic bladder (present) , Urinary retention (present) , Autism (present) , Impaired social interactions (present) , Pruritus (present) , … (more) Recurrent urinary tract infections (present) , Neurogenic bladder (present) , Urinary retention (present) , Autism (present) , Impaired social interactions (present) , Pruritus (present) , Seizure (present) , Absent speech (present) , Obesity (present) , Iron deficiency anemia (present) , Hyperammonemia (present) , Gastroesophageal reflux (present) , Abdominal pain (present) , Hiatus hernia (present) , Broad-based gait (present) , Aganglionic megacolon (present) , Headache (present) , Sleep abnormality (present) , Developmental regression (present) , Episodic vomiting (present) , Gastroparesis (present) , Gastrointestinal dysmotility (present) , Recurrent infections (present) , Recurrent candida infections (present) , Focal emotional seizure with laughing (present) , Intellectual disability, severe (present) , Chronic sinusitis (present) , Dermatographic urticaria (present) , Abnormal autonomic nervous system physiology (present) , Fatigue (present) , Chronic constipation (present) (less) Family history: no Age: 30-39 years Sex: female Tissue: Blood
Pathogenic (Sep 05, 2024)	no assertion criteria provided Method: clinical testing	MPO-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004104737.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The MPO c.2031-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported to be … (more) The MPO c.2031-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported to be causative for autosomal recessive myeloperoxidase deficiency (Marchetti et al. 2004. PubMed ID: 15108282; Vergnano et al. 2020. PubMed ID: 32758448). This variant is reported in 1.3% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Variants that disrupt the consensus splice acceptor site in MPO are expected to be pathogenic, and this variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/3632). This variant is interpreted as pathogenic. (less)
Pathogenic (Jan 06, 2020)	no assertion criteria provided Method: curation	Myeloperoxidase deficiency Affected status: unknown Allele origin: germline	Reproductive Health Research and Development, BGI Genomics Accession: SCV001142475.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020	Comment: NG_009629.1(NM_000250.1):c.2031-2A>C in the MPO gene has an allele frequency of 0.013 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant is predicted to cause … (more) NG_009629.1(NM_000250.1):c.2031-2A>C in the MPO gene has an allele frequency of 0.013 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It was detected in individual with autosomal recessive Myeloperoxidase deficiency, compound heterozygous with c.1566_1579del14 (PMID:15108282). The patient's phenotype is highly specific for the MPO gene (PMID:15108282). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied:PVS1; PM3; PP4; BS1. (less)
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001743601.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Likely pathogenic (May 01, 2022)	no assertion criteria provided Method: clinical testing	Myeloperoxidase deficiency Affected status: yes Allele origin: germline	Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska" Accession: SCV002573417.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022
not provided (-)	no classification provided Method: phenotyping only	Myeloperoxidase deficiency Affected status: yes Allele origin: maternal	GenomeConnect, ClinGen Accession: SCV000607007.1 First in ClinVar: Oct 14, 2017 Last updated: Oct 14, 2017	Comment: GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more) GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Tall stature (present) , Growth hormone excess (present) , Growth hormone deficiency (present) , Failure to thrive (present) , Short stature (present) , Hemihypertrophy (present) … (more) Tall stature (present) , Growth hormone excess (present) , Growth hormone deficiency (present) , Failure to thrive (present) , Short stature (present) , Hemihypertrophy (present) , Obesity (present) , Overgrowth (present) , Abnormality of the parathyroid physiology (present) , Hyperthyroidism (present) , Goiter (present) , Adrenal hyperplasia (present) , Hypogonadism (present) , Precocious puberty (present) , Diabetes insipidus (present) , Delayed puberty (present) , Type I diabetes mellitus (present) , Type II diabetes mellitus (present) , Oral-pharyngeal dysphagia (present) , Abnormality of the neck (present) , Abnormality of the mouth (present) , Abnormality of the oral cavity (present) , Abnormality of the optic nerve (present) , Hypermetropia (present) , Myopia (present) , Abnormality of vision (present) , Abnormality of eye movement (present) , Vertigo (present) , Tinnitus (present) , Sensorineural hearing impairment (present) , Abnormality of movement (present) , Memory impairment (present) , Abnormality of coordination (present) , Cognitive impairment (present) , Anxiety (present) , Autistic behavior (present) , Hyperpigmentation of the skin (present) , Multiple cafe-au-lait spots (present) , Joint hypermobility (present) , Abnormality of the curvature of the vertebral column (present) , Abnormality of muscle physiology (present) , Hypercholesterolemia (present) , Hypertension (present) , Abnormality of cardiovascular system morphology (present) , Syncope (present) , Cardiomyopathy (present) , Abnormal EKG (present) , Arrhythmia (present) , Asthma (present) , Abnormality of the intestine (present) , Gastrointestinal dysmotility (present) , Abnormality of the liver (present) , Abnormality of the stomach (present) , Abnormality of esophagus morphology (present) , Feeding difficulties (present) , Abnormality of urine homeostasis (present) , Abnormal renal morphology (present) , Abnormality of the bladder (present) , Rheumatoid arthritis (present) , Recurrent infections (present) , Abnormal inflammatory response (present) , Autoimmunity (present) , Abnormality of leukocytes (present) , Abnormality of erythrocytes (present) , Bleeding with minor or no trauma (present) , Abnormality of blood and blood-forming tissues (present) (less) Indication for testing: Diagnostic Age: 40-49 years Sex: female Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2016-09-09 Testing laboratory interpretation: Pathogenic
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Comment:

The 2031-2A>C variant in MPO has been previously identified in 1 compound heterozygous and 2 homozygous individuals with myeloperoxidase deficiency (Marchetti 2004). This variant is located in the 3' splice region and functional studies indicate that this variant leads to altered splicing (Marchetti 2004). In summary, the 2031-2A>C variant meets our criteria to be considered causative for myeloperoxidase deficiency (MPOD) in a recessive manner. However, the clinical relevance of MPOD is not well-established.

Comment:

Variant summary: MPO c.2031-2A>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing , and the predominant products were truncated MPO (Haskamp_2020), such mRNA products are not subject to NMD. The variant allele was found at a frequency of 0.0044 in 251174 control chromosomes in the gnomAD database, including 2 homozygotes (gnomAD v2), and in gnomAD v4 dataset, this vairant was found a frequency of 0.0066 in 1179978 control chromosomes in European (non-Finnish) group with 25 homozygotes, suggesting that the variant may be benign. c.2031-2A>C has been reported in the literature in at-least three individuals affected with Myeloperoxidase Deficiency (example, Marchetti_2004). Additionally, no pathogenic missense or in-frame changes from the last exon have been reported in ClinVar, suggesting the disrupted last exon may not be functionally important. The following publications have been ascertained in the context of this evaluation (PMID: 32758447, 15108282). ClinVar contains an entry for this variant (Variation ID: 3632). Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

Reported as a heterozygous germline variant in multiple individuals with myeloid neoplasms (PMID: 35761024); Splice site variant that destroys the canonical splice acceptor site in intron 11, and causes the activation of a cryptic splice site located 109 nucleotides upstream of the authentic splice site (PMID: 15108282); This variant is associated with the following publications: (PMID: 20974672, 25714468, 34662886, 35026467, 24385801, 17384005, 15108282, 26764160, 26822949, 27301573, 27827828, 30487145, 31980526, 32758448, 34426522, 32531373, 35761024, 36730508, 37868038, 38170104, 32758447)

Comment:

The MPO c.2031-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported to be causative for autosomal recessive myeloperoxidase deficiency (Marchetti et al. 2004. PubMed ID: 15108282; Vergnano et al. 2020. PubMed ID: 32758448). This variant is reported in 1.3% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Variants that disrupt the consensus splice acceptor site in MPO are expected to be pathogenic, and this variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/3632). This variant is interpreted as pathogenic.

Comment:

NG_009629.1(NM_000250.1):c.2031-2A>C in the MPO gene has an allele frequency of 0.013 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It was detected in individual with autosomal recessive Myeloperoxidase deficiency, compound heterozygous with c.1566_1579del14 (PMID:15108282). The patient's phenotype is highly specific for the MPO gene (PMID:15108282). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied:PVS1; PM3; PP4; BS1.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The genetic structure of the Turkish population reveals high levels of variation and admixture.	Kars ME	Proceedings of the National Academy of Sciences of the United States of America	2021	PMID: 34426522
Improving the diagnostic efficiency of primary immunodeficiencies with targeted next-generation sequencing.	Fusaro M	The Journal of allergy and clinical immunology	2021	PMID: 32531373
Loss-of-Function Myeloperoxidase Mutations Are Associated with Increased Neutrophil Counts and Pustular Skin Disease.	Vergnano M	American journal of human genetics	2020	PMID: 32758448
Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases.	Haskamp S	American journal of human genetics	2020	PMID: 32758447
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
High-frequency actionable pathogenic exome variants in an average-risk cohort.	Rego S	Cold Spring Harbor molecular case studies	2018	PMID: 30487145
Hereditary truncating mutations of DNA repair and other genes in BRCA1/BRCA2/PALB2-negatively tested breast cancer patients.	Lhota F	Clinical genetics	2016	PMID: 26822949
267 Spanish Exomes Reveal Population-Specific Differences in Disease-Related Genetic Variation.	Dopazo J	Molecular biology and evolution	2016	PMID: 26764160
Genetic characterization of myeloperoxidase deficiency in Italy.	Marchetti C	Human mutation	2004	PMID: 15108282
Clinical manifestation of myeloperoxidase deficiency.	Lanza F	Journal of molecular medicine (Berlin, Germany)	1998	PMID: 9766845
Hereditary myeloperoxidase deficiency.	Kitahara M	Blood	1981	PMID: 6260268
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Text-mined citations for rs35897051 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000250.2(MPO):c.2031-2A>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs35897051 ...