Submissions for variant NM_000152.5(GAA):c.1003G>A (p.Gly335Arg)

dbSNP: rs202095215

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001249005	SCV003852729	likely pathogenic	Glycogen storage disease, type II	2023-02-07	reviewed by expert panel	curation	The NM_000152.5:c.1003G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 335 (p.Gly335Arg). At least 4 patient(s) with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes, lymphocytes, muscle samples or were reported to be on enzyme replacement therapy for Pompe disease (PP4_Moderate) (PMIDs 31510962, 26497565, 31193175, 24685124). One of these probands is compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP, c.876C>G p.Tyr292X (PMID 31510962); the variants were confirmed in trans by familial testing (PM3). The highest population minor allele frequency in gnomAD v2.1.1 for this variant is 0.00003266 (1/30616 alleles) in the South Asian population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in COS7 or HEK293 cells resulted in 0.8% GAA activity in cells and evidence of abnormal synthesis and processing on Western blot, indicating that this variant may impact protein function (PMID 22644586)(PS3_Moderate). The computational predictor REVEL gives a score of 0.919 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant, c.1004G>A (p.Gly335Glu), in the same codon has been reported in a patient with Pompe disease (PMIDs 22644586, 32711049)s. However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP and, therefore, this evidence is not sufficient to meet PM5 at any strength. There is a ClinVar entry for this variant (Variation ID: 972790; 1 star review status) with one submitter classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PM3, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen LSD VCEP, February 7, 2023).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249005	SCV001422850	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Gly335Arg variant in GAA has been reported in four individuals with glycogen storage disease II (PMID: 24685124, 26497565, 18425781), and has been identified in 0.003% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs202095215). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies using COS-7 cells transfected with the variant provide some evidence that the p.Gly335Arg variant may impact protein function (PMID: 22644586). 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 pathogenic variant, resulting in a different amino acid change at the same position, p.Gly335Glu, has been reported in association with the disease in the literature and in ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 22644586, 24513544, 27649523; VariationID: 180142). The phenotype of an individual heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity being <10% of wild type consistent with disease (PMID: 26497565). In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease II in an autosomal recessive manner based on in vitro functional studies and another pathogenic variant at the same position. ACMG/AMP Criteria applied: PS3, PM2, PP3, PP4, PM5 (Richards 2015).
Invitae	RCV001249005	SCV003442521	pathogenic	Glycogen storage disease, type II	2022-08-31	criteria provided, single submitter	clinical testing	This variant disrupts the p.Gly335 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22644586, 32711049). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects GAA function (PMID: 22644586). 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. ClinVar contains an entry for this variant (Variation ID: 972790). This missense change has been observed in individual(s) with Pompe disease (PMID: 18425781, 26497565, 31510962). This variant is present in population databases (rs202095215, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 335 of the GAA protein (p.Gly335Arg).
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV001249005	SCV004011716	pathogenic	Glycogen storage disease, type II	2023-07-10	criteria provided, single submitter	clinical testing	The homozygous mis-sense variant c.1003G>A (p.Gly335Arg) has been identified in a proband with severe hypertrophied ventricles, respiratory distress, muscle weakness, hypotonia, proximal and distal muscle weakness of upper and lower limbs and feeding difficulties. this variant has been found in 0.0004% gnomAD (aggregated). This has been previously reported PMID:31510962
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV001249005	SCV004021940	pathogenic	Glycogen storage disease, type II	2023-07-27	criteria provided, single submitter	clinical testing	A Homozygous variation in exon 6 of the GAA gene that results in the amino acid substitution of Arginine for Glycine at codon 335 was detected. The observed variant c.1003G>A (p.Gly335Arg) has not been reported in the 1000 genomes and has a MAF of 0.0004% in the gnomAD database. The in silico prediction of the variant is disease causing by PolyPhen-2, SIFT, CADD and MutationTaster. In summary, the variant meets our criteria to be classified as pathogenic