Submissions for variant NM_000152.5(GAA):c.676C>G (p.Leu226Val)

gnomAD frequency: 0.00193  dbSNP: rs113085339

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001000493	SCV005089701	likely benign	Glycogen storage disease, type II	2024-05-07	reviewed by expert panel	curation	The NM_000152.5:c.676C>G variant in GAA is a missense variant predicted to cause substitution of leucine by valine at amino acid 226 (p.Leu226Val). The highest population minor allele frequency of this variant in gnomAD v2.1.1. is 0.006298 (156/24770 alleles) in the African/African American population which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BS1 (>0.005), and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.159 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). There are ten ClinVar entries for this variant (Variation ID:188476; 2 star review status) with eight submitters classifying the variant as likely benign and two as benign. In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS1, BP4. (Classification approved by the ClinGen Lysosomal Diseases VCEP on May 7, 2024)
Eurofins Ntd Llc (ga)	RCV000168658	SCV000228797	likely benign	not specified	2015-09-10	criteria provided, single submitter	clinical testing
GeneDx	RCV001721094	SCV000513089	benign	not provided	2019-01-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29149851)
Invitae	RCV001000493	SCV000626623	likely benign	Glycogen storage disease, type II	2024-02-01	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852728	SCV000995443	likely benign	Ventricular fibrillation	2019-05-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000493	SCV001157385	likely benign	Glycogen storage disease, type II	2018-09-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168658	SCV001362548	likely benign	not specified	2023-01-05	criteria provided, single submitter	clinical testing	Variant summary: GAA c.676C>G (p.Leu226Val) results in a conservative amino acid change located in the Galactose mutarotase, N-terminal barrel domain (IPR031727) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00059 in 242408 control chromosomes (1 homozygote), predominantly at a frequency of 0.0067 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) phenotype (0.0042), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.676C>G has been reported in the literature in an individual affected limb-girdle muscular weakness with a non-informative genotype (Johnson_2017). The report does not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001000493	SCV001423079	likely benign	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Leu226Val variant in GAA has not been reported in an individual with Glycogen Storage Disease II but has been reported in 1 European individual with unexplained limb-girdle muscle weakness (PMID: 29149851), and has been reported as a likely benign variant by EGL Genetic Diagnostics, GeneDx, and Invitae in ClinVar (Variation ID: 188476). This variant has been identified in 0.6298% (156/24770) of African chromosomes, 0.0622% (22/35358) of Latino chromosomes, and 0.0126% (16/127350) of European (non-Finnish) chromosomes, including 1 homozygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs113085339). This variant has been seen in the general population at a greater frequency than expected for Glycogen Storage Disease II and is consistent with a benign role. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4 (Richards 2015).
PreventionGenetics, part of Exact Sciences	RCV003907529	SCV004723323	likely benign	GAA-related disorder	2019-06-27	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Ambry Genetics	RCV004020009	SCV005032762	likely benign	Cardiovascular phenotype	2022-11-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Natera, Inc.	RCV001000493	SCV002091949	benign	Glycogen storage disease, type II	2019-12-13	no assertion criteria provided	clinical testing