ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1941C>G (p.Cys647Trp) (rs776948121)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665047 SCV000789104 likely pathogenic Glycogen storage disease, type II 2017-01-13 criteria provided, single submitter clinical testing
Invitae RCV000665047 SCV000827584 pathogenic Glycogen storage disease, type II 2018-07-02 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tryptophan at codon 647 of the GAA protein (p.Cys647Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant is present in population databases (rs776948121, ExAC 0.002%). This variant has been observed to be homozygous or in combination with another GAA variant in many individuals affected affected with infantile onset Pompe disease (PMID: 7981676, 22658377, 9535769, 19588081, 25681614, 17723315). Experimental studies have shown that this missense change abolishes enzyme activity in-vitro (PMID: 7981676). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000665047 SCV001422988 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Cys647Trp variant in GAA has been reported in at least seven individuals with glycogen storage disease II (PMID: 9535769, 17723315, 19588081, 25681614) and has been Identified in 0.002% (3/124712) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs776948121). 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 also been reported in ClinVar as Pathogenic by Invitae and as Likely Pathogenic by Counsyl (VariationID: 550327). In vitro functional studies provide some evidence that the p.Cys647Trp variant may impact protein function (PMID: 9535769). However, these types of assays may not accurately represent biological function. The phenotype of an individual homozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in fibroblasts being <1% of wild type, consistent with disease (PMID: 9535769, 17723315). 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, the presence of this variant in homozygous individuals in individuals with glycogen storage disease II increases the likelihood that the p.Cys647Trp variant is pathogenic (PMID: 9535769, 17723315). In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease II in an autosomal recessive manner based on its presence in affected individuals in combination with other pathogenic variants or in a homozygous state, in vitro functional studies demonstrating markedly reduced expression, and low frequency in the general population. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP3, PP4 (Richards 2015).

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