Submissions for variant NM_000152.5(GAA):c.1447G>A (p.Gly483Arg)

gnomAD frequency: 0.00001  dbSNP: rs770590394

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000664619	SCV005089702	pathogenic	Glycogen storage disease, type II	2024-05-07	reviewed by expert panel	curation	The NM_000152.5:c.1447G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 483 (p.Gly483Arg). At least 7 individuals with this variant have been reported to have Pompe disease. Of these individuals, 3 were compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, with unknown phase, including c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1) (0.5 points, PMID: 30214072, 33073009), c.525delT (ClinVar Variation ID: 4033, SCV001443331.1) (0.5 points, PMID: 33073009), and c.32-13T>G (ClinVar Variation ID: 4027) (0.5 points, PMID: 21972175, 29289479). In addition, 2 individuals were homozygous for the variant (2 x 0.5 points. PMID: 36572041, Revvity Omics Clinical Laboratory data) (PM3_Strong). Two more patients have been described with the variant and another variant, either c.-32-17_-32-10delinsT CCCTGCTGAGCCTCCTACA GGCCTCCCGC (PMID: 25687635) or c.569G>A (p.Arg190His) (PMID: 23000108). The allelic data from these patients will be used in the classification the second variant and is not included here to avoid circular logic. At least 4 individuals have GAA activity <10% normal in lymphocytes/leukocytes/muscle samples/<30% normal in cultured fibroblasts / or were reported to be on enzyme replacement therapy for Pompe disease (PMIDs: 23000108, 36572041, 33073009) (PP4_Moderate). This variant has a minor allele frequency of 0.00010(1/10306) in the African population in gnomAD v2.1.1, which is lower than the ClinGen Lysosomal Diseases VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Expression of the variant in COS7 cells resulted in 0% GAA activity in cells and 0% in medium, and evidence of abnormal synthesis and processing on Western blot, indicating that this variant may impact protein function (PMID: 18425781)(PS3_Moderate). The computational predictor REVEL gives a score of 0.822 which is above the thresholds predicting a damaging (>0.7) impact on GAA function and therefore meets this criterion (PS3). There is a ClinVar entry for this variant (Variation ID: 285157). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specification of the ClinGen Lysosomal Diseases VCEP: PS3_moderate, PM2_supporting, PM3_strong, PP3, PP4_moderate. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 7, 2024)
Counsyl	RCV000664619	SCV000788614	likely pathogenic	Glycogen storage disease, type II	2017-04-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000664619	SCV000831059	pathogenic	Glycogen storage disease, type II	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 483 of the GAA protein (p.Gly483Arg). This variant is present in population databases (rs770590394, gnomAD 0.007%). This missense change has been observed in individual(s) with Pompe disease (PMID: 18425781, 19588081, 21972175, 23000108, 29122469). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 285157). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 18425781, 23000108). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000664619	SCV001422809	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The heterozygous p.Gly483Arg variant in GAA has been reported in 5 individuals with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 19588081, 24383498, 23000108), and has been identified in 0.006% (1/16208) of African chromosomes and 0.001% (1/113308) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs770590394). 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 been reported as a VUS by EGL Genetic Diagnostics, likely pathogenic variant by Counsyl, and pathogenic by Invitae in ClinVar (Variation ID: 285157). In vitro functional studies provide some evidence that the p.Gly483Arg variant may impact protein function (PMID: 18425781). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. A rare, likely pathogenic variant at the the same position, p.Gly483Val, has been reported in association with disease, slightly supporting that a change at this position may not be tolerated (PMID: 22644586, 31193175). This variant has been reported in combination with other variants associated with disease and in individuals with Glycogen Storage Disease II (PMID: 19588081, 24383498, 23000108; Variation ID: 371622, 4027, 188809). The phenotype of the 2 compound heterozygous siblings is highly specific for Glycogen Storage Disease II based on GAA activity assays with muscle and fibroblast cells as well as a Western Blot with fibroblast cells (PMID: 23000108). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PP3, PP4, PM5_Supporting (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000664619	SCV001437416	pathogenic	Glycogen storage disease, type II	2020-09-11	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1447G>A (p.Gly483Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250890 control chromosomes (gnomAD). c.1447G>A has been reported in the literature in the compound heterozygous and homozygous state, in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. Kroos_2008, Ebrahim_2012, Wens_2012, Verma_2017, Kishnani_2019). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant causes a considerable reduction in GAA enzyme activity (e.g. Kroos_2008, Wens_2012). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000664619	SCV001810607	likely pathogenic	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000664619	SCV004197824	pathogenic	Glycogen storage disease, type II	2024-03-07	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000278497	SCV000338058	uncertain significance	not provided	2015-12-08	flagged submission	clinical testing
Natera, Inc.	RCV000664619	SCV002092037	pathogenic	Glycogen storage disease, type II	2020-09-10	no assertion criteria provided	clinical testing