ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1781G>A (p.Arg594His)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Institute Rare Disease Group,Broad Institute RCV001248866 SCV001422541 pathogenic Glycoprotein storage disease 2020-01-22 no assertion criteria provided curation The p.Arg594His variant in GAA has been reported in four individuals with glycogen storage disease II (PMID: 24444888, 30155607, 25526786, 22644586) and has been identified in 0.010% (1/9994) of Ashkenazi Jewish chromosomes and 0.001% (1/111938) of European (non-Finnish chromosomes) by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs775450536). 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-7 cells and medium transfected with the variant provide some evidence that the p.Arg594His variant may impact protein function (PMID: 22644586). However, these types of assays may not accurately represent biological function. The phenotype of an individual heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity being <2% of wild type, consistent with disease (PMID: 24444888). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with reported pathogenic variant p.Asp645Glu (VariationID: 4029, PMID: 24444888) and in an individual with glycogen storage disease II increases the likelihood that the p.Arg594His variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease II in an autosomal recessive manner based on in vitro functional studies, low frequency in the general population, and an occurrence with another pathogenic variant in an affected individual. ACMG/AMP Criteria applied: PS3, PM2, PM5_supporting, PM3_supporting, PP3, PP4 (Richards 2015).

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