Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Broad Center for Mendelian Genomics, |
RCV001248924 | SCV001422692 | likely pathogenic | Glycogen storage disease, type II | 2020-01-14 | criteria provided, single submitter | curation | The p.Gly615Glu variant in GAA has been reported in one individual with glycogen storage disease II (PMID: 15986226) and has been identified in 0.003% (1/34196) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1243515778). 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.Gly615Arg, has been reported in association with disease in ClinVar and the literature, slightly supporting that a change at this position may not be tolerated (PMID: 16860134, 18458862, 10338092, 18607768, 15366815; Variation ID: 188786). The phenotype of an individual heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in muscle being 2% of wild type, consistent with disease (PMID: 15986226). Additionally, the presence of this variant in combination with reported pathogenic variant c.-32-13T>G (VariationID: 4027; PMID: 15986226) and in an individual with glycogen storage disease II increases the likelihood that the p.Gly615Glu variant is pathogenic. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3_supporting, PP3, PM5_supporting, PP4 (Richards 2015). |
| Baylor Genetics | RCV001248924 | SCV004197857 | likely pathogenic | Glycogen storage disease, type II | 2023-03-10 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001248924 | SCV004296883 | pathogenic | Glycogen storage disease, type II | 2023-05-22 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 615 of the GAA protein (p.Gly615Glu). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly615 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15366815, 16860134, 25037089). 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: 972758). This missense change has been observed in individual(s) with Pompe disease (PMID: 15986226, 31086307). This variant is present in population databases (no rsID available, gnomAD 0.003%). |