Submissions for variant NM_000152.5(GAA):c.2152G>A (p.Val718Ile)

gnomAD frequency: 0.00021  dbSNP: rs141017311

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000382817	SCV002540666	likely benign	Glycogen storage disease, type II	2024-05-21	reviewed by expert panel	curation	The NM_000152.5:c.2152G>A variant in GAA is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 718 (p.Val718Ile). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.00011 in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP's threshold (<0.001) for PM2_Supporting. The highest minor allele frequency in any population is 0.005329 in the Ashkenazi Jewish population. This allele frequency meets the criteria for BS1 (>0.005) but BS1 was not applied because the Ashkenazi Jewish population is not defined as a continental population (PMID: 30311383). When expressed in COS-7 cells, this variant does not result in significantly reduced GAA activity, and the gene product is normally synthesized and/or processed (PMID 22644586, 31228295) (BS3_Supporting). The computational predictor REVEL gives a score of 0.193 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. The computational splicing predictor SpliceAI suggests that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 281232) with four submitters classifying the variant as a variant of uncertain significance, four as likely benign and one 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: BP4, BS3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP on May 21, 2024)
Eurofins Ntd Llc (ga)	RCV000675239	SCV000331842	uncertain significance	not provided	2018-03-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000382817	SCV000407293	uncertain significance	Glycogen storage disease, type II	2018-01-13	criteria provided, single submitter	clinical testing	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000265982	SCV000518838	likely benign	not specified	2017-04-20	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000382817	SCV000626547	likely benign	Glycogen storage disease, type II	2024-01-28	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852733	SCV000995448	likely benign	Hypertrophic cardiomyopathy	2017-06-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000675239	SCV001151431	uncertain significance	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000382817	SCV001423078	benign	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Val718Ile variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported as a VUS (by EGL, Illumina, and Invitae) and a likely benign variant (by GeneDx and Mayo Clinic Genetic Testing Laboratories) in ClinVar (Variation ID: 281232). This variant has been identified in 0.533% (51/9570) of Ashkenazi Jewish chromosomes, 0.011% (3/27108) of South Asian chromosomes and 0.007% (8/112166) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs141017311). 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. In vitro functional studies provide some evidence that the p.Val718Ile variant may have no impact on GAA activity or protein levels (PMID: 22644586). However, these types of assays may not accurately represent biological function. 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, this variant meets criteria to be classified as benign for Glycogen Storage Disease II in an autosomal recessive manner based on its frequency in the general population and well-established functional studies. ACMG/AMP Criteria applied: BS3, BS1, BP4 (Richards 2015).
Genome-Nilou Lab	RCV000382817	SCV001810175	uncertain significance	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002429212	SCV002731243	likely benign	Cardiovascular phenotype	2019-08-12	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000675239	SCV000800885	likely benign	not provided	2017-05-10	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000382817	SCV001459749	likely benign	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing