VCV000092486.40 - ClinVar

NM_000152.5(GAA):c.596A>G (p.His199Arg)

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.

(16)

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.

Benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000152.5(GAA):c.596A>G (p.His199Arg)

Variation ID: 92486 Accession: VCV000092486.40

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q25.3 17: 80105798 (GRCh38) [ NCBI UCSC ] 17: 78079597 (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	May 17, 2014	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000152.5:c.596A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000143.2:p.His199Arg	missense
NM_001079803.3:c.596A>G	NP_001073271.1:p.His199Arg	missense
NM_001079804.3:c.596A>G	NP_001073272.1:p.His199Arg	missense
NC_000017.11:g.80105798A>G
NC_000017.10:g.78079597A>G
NG_009822.1:g.9243A>G
LRG_673:g.9243A>G
LRG_673t1:c.596A>G	LRG_673p1:p.His199Arg
	P10253:p.His199Arg

... more HGVS ... less HGVS

Protein change

H199R

Other names

Canonical SPDI

NC_000017.11:80105797:A: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.

0.39916 (A)

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

1000 Genomes Project 30x 0.59931

1000 Genomes Project 0.60084

Trans-Omics for Precision Medicine (TOPMed) 0.63755

The Genome Aggregation Database (gnomAD) 0.65667

The Genome Aggregation Database (gnomAD), exomes 0.66745

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.67254

Exome Aggregation Consortium (ExAC) 0.67455

Links

ClinGen: CA145785 UniProtKB: P10253#VAR_004286 dbSNP: rs1042393 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.
GAA		-	-	GRCh38 GRCh38 GRCh37	2809	2861

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.
not specified	Benign (5)	criteria provided, multiple submitters, no conflicts	Sep 4, 2018	RCV000078183.28
Glycogen storage disease, type II	Benign (6)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000275148.25
not provided	Benign (4)	criteria provided, multiple submitters, no conflicts	Mar 3, 2015	RCV000675217.17
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Dec 11, 2018	RCV002354274.9

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.
Benign (Aug 15, 2013)	criteria provided, single submitter (ACMG Guidelines, 2007) Method: clinical testing	AllHighlyPenetrant (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000151263.1 First in ClinVar: May 17, 2014 Last updated: May 17, 2014
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Glycogen storage disease, type II Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000407265.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001852393.1 First in ClinVar: Sep 12, 2021 Last updated: Sep 12, 2021
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Glycogen storage disease, type II Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001725518.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024
Benign (Dec 11, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002657839.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005248719.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000302691.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Aug 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease, type II Affected status: unknown Allele origin: germline	Phosphorus, Inc. Accession: SCV000679769.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (3) PubMed: 18414213‚ 23757202‚ 25741868 Number of individuals with the variant: 20
Benign (Sep 04, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000110021.8 First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GAA Number of individuals with the variant: 112 Sex: mixed
Benign (Jun 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease, type II Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001738010.1 First in ClinVar: Jun 26, 2021 Last updated: Jun 26, 2021	Sex: mixed
Benign (Oct 19, 2015)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000800861.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001926960.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	Glycogen storage disease, type II Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733723.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Uncertain significance (-)	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: SCV001551027.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 77.976% in gnomAD_ExomesFounderPop) based on … (more) multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 77.976% in gnomAD_ExomesFounderPop) based on the frequency threshold of 2.76% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease.8 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. (less)
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001955522.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Benign (Nov 18, 2019)	no assertion criteria provided Method: clinical testing	Glycogen storage disease type II Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002091939.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
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Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 77.976% in gnomAD_ExomesFounderPop) based on the frequency threshold of 2.76% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease.8 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.

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
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
Free the data: one laboratory's approach to knowledge-based genomic variant classification and preparation for EMR integration of genomic data.	Bean LJ	Human mutation	2013	PMID: 23757202
ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.	Richards CS	Genetics in medicine : official journal of the American College of Medical Genetics	2008	PMID: 18414213
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GAA	-	-	-	-

Text-mined citations for rs1042393 ...

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_000152.5(GAA):c.596A>G (p.His199Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1042393 ...