ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1447G>A (p.Gly483Arg) (rs770590394)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000278497 SCV000338058 uncertain significance not provided 2015-12-08 criteria provided, single submitter clinical testing
Counsyl RCV000664619 SCV000788614 likely pathogenic Glycogen storage disease, type II 2017-04-28 criteria provided, single submitter clinical testing
Invitae RCV000664619 SCV000831059 pathogenic Glycogen storage disease, type II 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 483 of the GAA protein (p.Gly483Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs770590394, ExAC 0.01%). This variant has been observed to segregate with Pompe disease in a family (PMID: 23000108), and has been reported in several individuals affected with Pompe disease (PMID: 18425781, 19588081, 21972175, 29122469). ClinVar contains an entry for this variant (Variation ID: 285157). Experimental studies have shown that this missense change results in reduced GAA enzymatic activity (PMID: 18425781, 23000108). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000664619 SCV001422809 likely pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided 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).

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