ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1933G>T (p.Asp645Tyr) (rs368438393)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672387 SCV000797486 likely pathogenic Glycogen storage disease, type II 2018-01-28 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000672387 SCV001422989 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Asp645Tyr variant in GAA has been reported in four individuals with glycogen storage disease II, segregated with disease in 2 affected relatives from 1 family (PMID: 18425781, 17616415; DOI: 10.1016/j.jns.2015.08.1211) and has been identified in 0.007% (1/15154) of African chromosomes and 0.003% (1/33952) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368438393). 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 likely pathogenic by Counsyl (VariationID: 556386). In vitro studies using cells transfected with the variant provide some evidence that the p.Asp645Tyr variant may impact protein function (PMID: 18425781). However, these types of assays may not accurately represent biological function. Three additional pathogenic variants, resulting in a different amino acid change at the same position (p.Asp645Asn, p.Asp645His, and p.Asp645Glu) have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (VariationID: 188728, 189013, 4029). 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 phenotype of an individual heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in fibroblasts being <20% of wild type, consistent with disease (PMID: 17616415). Additionally, the presence of this variant in combination with reported pathogenic variant c.-32-13T>G (VariationID: 4027; PMID: 17616415, https://doi.org/10.1016/j.jns.2015.08.1211) and in individuals with glycogen storage disease II silghtly increases the likelihood that the p.Asp645Tyr 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 functional studies demonstrating a potential impact on the protein, previous reports of other pathogenic variants at the same location, and the presence of the variant in combination with a pathogenic variant in an affected individual. ACMG/AMP Criteria applied: PM5_Strong, PS3, PM2, PM3_Supporting, PP3, PP4 (Richards 2015).

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