Submissions for variant NM_000152.5(GAA):c.1432G>A (p.Gly478Arg)

dbSNP: rs778068209

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000666316	SCV005619832	pathogenic	Glycogen storage disease, type II	2024-11-05	reviewed by expert panel	curation	The NM_000152.5:c.1432G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 478 (p.Gly478Arg). At least seven probands with symptoms consistent with infantile-onset-Pompe disease or late-onset Pompe disease with documented deficiency of GAA activity have been reported with this variant (PMIDs 25998610, 25213570, 17616415, 28394184) (PP4_Moderate). Six of these probands are compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen Lysosomal Diseases VCEP; the variants were confirmed in trans by parental testing for one of the patients (PM3_Strong). The highest population minor allele frequency in gnomAD v2.1,1 is 0.00002895 (Latino) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_supporting, meeting this criterion. Expression of the variant in COS7 cells resulted in <2% GAA activity in cells, indicating that this variant may impact protein function (PMID 22253258, 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.954 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 551295, 2 star review status) with 2 submitters classifying the variant as Likely Pathogenic and 2 submitters classfying the variant as Pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic 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): PM3_Strong, PP4_Moderate, PS3_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 5, 2024)
Counsyl	RCV000666316	SCV000790588	likely pathogenic	Glycogen storage disease, type II	2017-04-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000666316	SCV001216608	pathogenic	Glycogen storage disease, type II	2022-08-24	criteria provided, single submitter	clinical testing	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 create or strengthen a splice site. Experimental studies have shown that this missense change affects GAA function (PMID: 14695532, 28592009). 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: 551295). This missense change has been observed in individual(s) with Pompe disease (PMID: 14695532, 17616415, 25213570, 25998610, 28394184, 28592009). This variant is present in population databases (rs778068209, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 478 of the GAA protein (p.Gly478Arg).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000666316	SCV001422701	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Gly478Arg variant in GAA has been reported in seven individuals with glycogen storage disease II (PMID: 28394184, 25213570, 25998610, 17616415, 14695532) and has also been reported as likely pathogenic by Counsyl in ClinVar (VariationID: 551295). This variant has been identified in 0.003% (1/34538) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs778068209). 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 cells transfected with the variant provide some evidence that the p.Gly478Arg variant may impact protein function (PMID: 14695532, 19862843). 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. Additionally, this variant was reported in combination with reported pathogenic variants in individuals with glycogen storage disease II (VariationID: 4027, 194154, 403712; PMID: 25998610, 17616415, 28394184, 25213570). 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 (Richards 2015).
Baylor Genetics	RCV000666316	SCV005058720	pathogenic	Glycogen storage disease, type II	2024-03-30	criteria provided, single submitter	clinical testing