Submissions for variant NM_000152.5(GAA):c.1504A>G (p.Met502Val)

gnomAD frequency: 0.00007  dbSNP: rs376067362

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000526491	SCV004227907	uncertain significance	Glycogen storage disease, type II	2023-10-01	reviewed by expert panel	curation	The NM_000152.5:c.1504A>G variant in GAA is a missense variant predicted to cause substitution of methionine by valine at amino acid 502 (p.Met502Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00010 (13/128968 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.805 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). At least 3 individuals with this variant had documented GAA deficiency activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot or were noted to have deficient GAA activity but results were not provided. One individual was a compound heterozygous for the variant and the pathogenic c.-32-13T>G variant, not confirmed in trans (PMID: 24158270) and one individual was confirmed in trans with the pathogenic variants c.-32-13T>G, c.1856G>A (p.Ser619Asn) in cis (internal laboratory data). However no symptoms of Pompe disease have been reported for these patients and therefore PM3 and PP4 will not be applied. There is a ClinVar entry for this variant (Variation ID: 439746, 2 star review status) with 12 submitters classifying the variant as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PM2_Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 1, 2023).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506584	SCV000603776	uncertain significance	not specified	2016-10-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526491	SCV000626519	uncertain significance	Glycogen storage disease, type II	2022-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 502 of the GAA protein (p.Met502Val). This variant is present in population databases (rs376067362, gnomAD 0.01%). This missense change has been observed in individual(s) with glycogen storage disease type II (PMID: 24158270, 33202836; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 439746). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Eurofins Ntd Llc (ga)	RCV000726935	SCV000704283	uncertain significance	not provided	2016-12-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000526491	SCV000915788	uncertain significance	Glycogen storage disease, type II	2018-12-07	criteria provided, single submitter	clinical testing	The GAA c.1504A>G (p.Met502Val) missense variant has been reported in one study and found in one individual with late-onset glycogen storage disease II in a compound heterozygous state with a known pathogenic allele (Remiche et al. 2014). The p.Met502Val variant was absent from 100 ethnically matched healthy controls but is reported at a frequency of 0.000121 in the European (non-Finnish) population of the Exome Aggregation Consortium. Although functional studies were not available, Remiche et al. (2014) reported muscle GAA enzyme residual activity in the affected individual to be 14% of normal. Based on the limited evidence, the p.Met502Val variant is classified as a variant of unknown significance, but suspicious for pathogenicity for glycogen storage disease, type II. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000526491	SCV001422659	uncertain significance	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The heterozygous p.Met502Val variant in GAA has been reported in one Italian individual with Glycogen Storage Disease II (PMID: 24158270). This variant has been identified in 0.010% (13/128968) of European (non-Finnish) chromosomes and 0.003% (1/35432) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs376067362). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported as a VUS by Invitae, EGL Genetic Diagnostics, Illumina, and ARUP Laboratories in ClinVar (Variation ID: 439746). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The Methionine (Met) at position 502 is not highly conserved in mammals and evolutionary distant species, and one species (American alligator) carries a Valine (Val), raising the possibility that this change at this position may be tolerated. This variant was reported in combination with a reported pathogenic variant and in an individual with Glycogen Storage Disease II (PMID: 24158270). In summary, the clinical significance of the p.Met502Val variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3 (Richards 2015).
GeneDx	RCV000726935	SCV001830868	uncertain significance	not provided	2021-03-17	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33202836, 30985853, 24158270)
Genome-Nilou Lab	RCV000526491	SCV002027275	uncertain significance	Glycogen storage disease, type II	2021-09-05	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000526491	SCV002581633	uncertain significance	Glycogen storage disease, type II	2022-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000526491	SCV002797145	uncertain significance	Glycogen storage disease, type II	2022-02-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000726935	SCV003828442	uncertain significance	not provided	2023-04-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000526491	SCV003835031	likely pathogenic	Glycogen storage disease, type II	2024-03-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000526491	SCV001455618	uncertain significance	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing