Submissions for variant NM_000152.5(GAA):c.1562A>T (p.Glu521Val)

dbSNP: rs1455277014

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248926	SCV001422695	uncertain significance	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Glu521Val variant in GAA has been reported in two Chinese individuals and has been identified in 0.005% (1/18390) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1455277014). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Glu521Lys, has been reported in association with glycogen storage disease II in the literature and ClinVar, slightly supporting that this variant may not be tolerated (VariationID: 4022; PMID: 1898413, 21605996, 22704482, 22676651). Additionally, this variant has been reported in combination with a likely pathogenic variant and in an individual with glycogen storage disease II (PMID: 2556786). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PM5_supporting (Richards 2015).
Revvity Omics, Revvity	RCV001780190	SCV002025226	likely pathogenic	not provided	2021-07-29	criteria provided, single submitter	clinical testing
Invitae	RCV001248926	SCV003442564	pathogenic	Glycogen storage disease, type II	2023-04-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu521 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1898413, 17723315). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 972760). This missense change has been observed in individuals with Pompe disease (PMID: 25526786, 28394184). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 521 of the GAA protein (p.Glu521Val).