VCV000092484.36 - ClinVar

NM_000152.5(GAA):c.324T>C (p.Cys108=)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Benign

for Glycogen storage disease, type II

Classification is based on the expert panel submission

Jan 2020 by ClinGen Lysosomal Storage Disorder Variant Curation Expert …

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000152.5(GAA):c.324T>C (p.Cys108=)

Variation ID: 92484 Accession: VCV000092484.36

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q25.3 17: 80104910 (GRCh38) [ NCBI UCSC ] 17: 78078709 (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	Feb 25, 2025	Jan 21, 2020

HGVS

Nucleotide	Protein	Molecular consequence
NM_000152.5(GAA):c.324T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000152.5:c.324T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000143.2:p.Cys108=	synonymous
NM_001079803.3:c.324T>C	NP_001073271.1:p.Cys108=	synonymous
NM_001079804.3:c.324T>C	NP_001073272.1:p.Cys108=	synonymous
NC_000017.11:g.80104910T>C
NC_000017.10:g.78078709T>C
NG_009822.1:g.8355T>C
LRG_673:g.8355T>C
LRG_673t1:c.324T>C

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000017.11:80104909:T:C

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.

0.28554 (T)

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

The Genome Aggregation Database (gnomAD), exomes 0.72276

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.73158

Exome Aggregation Consortium (ExAC) 0.73668

Trans-Omics for Precision Medicine (TOPMed) 0.70361

1000 Genomes Project 30x 0.71377

1000 Genomes Project 0.71446

The Genome Aggregation Database (gnomAD) 0.71989

Links

ClinGen: CA145781 dbSNP: rs1800300 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.
CCDC40		Gene associated with autosomal recessive phenotype	Not yet evaluated	GRCh38 GRCh38 GRCh37	1029	1073
GAA		Gene associated with autosomal recessive phenotype	Not yet evaluated	GRCh38 GRCh38 GRCh37	2926	2979

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 (6)	criteria provided, multiple submitters, no conflicts	Sep 4, 2018	RCV000078180.26
Glycogen storage disease, type II	Benign (7)	reviewed by expert panel	Jan 21, 2020	RCV000284275.21
Primary ciliary dyskinesia	Benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000299885.7
not provided	Benign (5)	criteria provided, multiple submitters, no conflicts	May 3, 2017	RCV000587169.11
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Dec 28, 2015	RCV002321569.3

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 (Jan 21, 2020) C Contributing to aggregate classification	reviewed by expert panel (ClinGen LSD ACMG Specifications v1) Method: curation	Glycogen storage disease, type II (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel FDA Recognized Database Accession: SCV001371707.1 First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/1e551ab9-03f5-4129-9604-a9da6ebea09c Comment: The highest continental population minor allele frequency for c.324T>C (p.Cys108=) in gnomAD v2.1.1 is 0.81776 in the South Asian population. This is higher than the … (more) The highest continental population minor allele frequency for c.324T>C (p.Cys108=) in gnomAD v2.1.1 is 0.81776 in the South Asian population. This is higher than the ClinGen LSD VCEP's BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 92484, two star review status), with 10 submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. (less)
Benign (Aug 15, 2013) N Not contributing to aggregate classification	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: SCV000151260.1 First in ClinVar: May 17, 2014 Last updated: May 17, 2014
Benign (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000302686.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Jun 14, 2016) N Not contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Primary Ciliary Dyskinesia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000483696.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Benign (Aug 01, 2017) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease, type II Affected status: unknown Allele origin: germline	Phosphorus, Inc. Accession: SCV000679832.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (3) PubMed: 18414213‚ 23757202‚ 25741868 Number of individuals with the variant: 21
Benign (May 03, 2017) N Not contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000695661.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Comment: Variant summary: The GAA c.324T>C (p.Cys108Cys) variant involves the alteration of a non-conserved nucleotide causing a synonymous change and 5/5 splice prediction tools predict no … (more) Variant summary: The GAA c.324T>C (p.Cys108Cys) variant involves the alteration of a non-conserved nucleotide causing a synonymous change and 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 86202/117014 control chromosomes (32095 homozygotes) at a frequency of 0.7366811, indicating the C allele is the major allele. This frequency is approximately 175 times the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant has been classified as benign. (less)
Benign (Sep 04, 2018) N Not contributing to aggregate classification	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: SCV000110018.8 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: 135 Zygosity: Homozygote, Single Heterozygote Sex: mixed
Benign (May 08, 2017) N Not contributing to aggregate classification	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000711747.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Comment: p.Cys108Cys in exon 3 of GAA: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue … (more) p.Cys108Cys in exon 3 of GAA: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 82% (13463/16390) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs1800300). (less) Number of individuals with the variant: 1
Benign (Jun 10, 2021) N Not contributing to aggregate classification	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: SCV001738007.1 First in ClinVar: Jun 26, 2021 Last updated: Jun 26, 2021	Sex: mixed
Benign (Mar 03, 2015) N Not contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001937502.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (Dec 28, 2015) N Not contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002609864.2 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 (Feb 04, 2025) N Not contributing to aggregate classification	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: SCV001730023.5 First in ClinVar: Jun 15, 2021 Last updated: Feb 25, 2025
Benign (Jun 14, 2016) N Not contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Glycogen Storage Disease, Type II Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000407257.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Benign (-) N Not contributing to aggregate classification	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: SCV005248712.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Oct 19, 2015) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000800857.1 First in ClinVar: Aug 04, 2018 Last updated: Aug 04, 2018
Benign (Sep 16, 2020) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Glycogen storage disease type II Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001453582.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Uncertain significance (-) N Not contributing to aggregate classification	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: SCV001553818.1 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: 82.142% in ExAC) based on … (more) multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 82.142% in ExAC) 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.10 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.A synonymous variant not located in a splice region. (less)
Benign (-) N Not contributing to aggregate classification	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: SCV001954062.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Benign (-) N Not contributing to aggregate classification	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: SCV000733721.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (-) N Not contributing to aggregate classification	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: SCV001926273.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
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Comment:

The highest continental population minor allele frequency for c.324T>C (p.Cys108=) in gnomAD v2.1.1 is 0.81776 in the South Asian population. This is higher than the ClinGen LSD VCEP's BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 92484, two star review status), with 10 submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1.

Comment:

Variant summary: The GAA c.324T>C (p.Cys108Cys) variant involves the alteration of a non-conserved nucleotide causing a synonymous change and 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 86202/117014 control chromosomes (32095 homozygotes) at a frequency of 0.7366811, indicating the C allele is the major allele. This frequency is approximately 175 times the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant has been classified as benign.

Comment:

p.Cys108Cys in exon 3 of GAA: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 82% (13463/16390) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs1800300).

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: 82.142% in ExAC) 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.10 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.A synonymous variant not located in a splice region.

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	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/1e551ab9-03f5-4129-9604-a9da6ebea09c	-	-	-	-

Text-mined citations for rs1800300 ...

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 Mar 16, 2025

ClinVar Genomic variation as it relates to human health

NM_000152.5(GAA):c.324T>C (p.Cys108=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1800300 ...