ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2236T>G (p.Trp746Gly) (rs1479740763)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672437 SCV000797542 uncertain significance Glycogen storage disease, type II 2018-02-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000672437 SCV001361532 likely pathogenic Glycogen storage disease, type II 2019-01-08 criteria provided, single submitter clinical testing Variant summary: GAA c.2236T>G (p.Trp746Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Two different variants affecting the same codon, namely c.2238G>C (p.Trp746Cys, internal database) and c.2236T>C (p.Trp746Arg, Emory EmVClass variant database) have been reported as Pathogenic and Likely Pathogenic respectively. This suggests that the variant may impact a functionally relevant residue in the GAA protein. The variant allele was found at a frequency of 3.2e-05 in 30938 control chromosomes (gnomAD, genome dataset). c.2236T>G has been reported in the literature in a heterozygous individual, found during newborn screening, who had a low lymphocyte GAA activity (Labrousse 2010). This report does not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). At least one publication reports experimental evidence evaluating an impact on protein function (Nino 2012). The most pronounced variant effect results in <10% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000672437 SCV001422965 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Trp746Gly variant in GAA has been reported in two individuals with glycogen storage disease II (PMID: 21488293, 20080426) and has also been reported in ClinVar (VariationID: 556431) as a VUS by Counsyl. Data from large population studies is insufficient to assess the frequency of this variant. In vitro functional studies using HEK-293 cells and medium transfected with the variant provide some evidence that the p.Trp746Gly variant may impact protein function (PMID: 23430493). However, these types of assays may not accurately represent biological function. Three additional pathogenic and likely pathogenic variants, resulting in a different amino acid change at the same position, p.Trp746Ser, p.Trp746Cys, and p.Trp746Arg, have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 188484, 265160, 499293). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 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 and multiple reported pathogenic variants in the same codon. ACMG/AMP Criteria applied: PM5_strong, PS3, PP3 (Richards 2015).

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