ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.781G>A (p.Ala261Thr) (rs543360994)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000536776 SCV000626640 uncertain significance Glycogen storage disease, type II 2019-03-12 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 261 of the GAA protein (p.Ala261Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs543360994, ExAC 0.01%) but has not been reported in the literature in individuals with a GAA-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Department of Pediatrics, Division of Medical Genetics, Faculty of Medicine Ramathibodi Hospital, Mahidol University RCV000536776 SCV000925965 pathogenic Glycogen storage disease, type II 2019-07-10 no assertion criteria provided research The c.781G>A (p.A261T) is present in population database (rs543360994, ExAC 0.00002%). This variant has not been reported in the literature in individuals with GAA-related disease. ClinVar contains an entry for this variant (Variation ID: 456438). It was reported to have uncertain impact on protein function and there is no indication that it causes disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, Polyphen-2, PredictSNP2, CADD, DANN, FATHMM, and FunSeq2) all suggest that this variant is damaging/deleterious. Our study provided evident supported the impact of amino acid substitution at this position on GAA function. In vitro expression analysis of c.781G>A (p.A261T) indicates that this variant yielded partial reduction of enzyme activity and impaired GAA processing and transportation. We interpret c.781G>A (p.A261T) as a pathogenic variant.

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