ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1478C>T (p.Pro493Leu) (rs148842275)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000443985 SCV000516792 likely pathogenic not provided 2017-06-26 criteria provided, single submitter clinical testing The P493L variant in the GAA gene has been reported previously in the presence of a second GAA variant, in several unrelated individuals with adult-onset Glycogen Storage Disease type II (Lukacs et al., 2010; Katona et al., 2014; Vill et al., 2015). The P493L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P493L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P493L as a pathogenic variant.
Invitae RCV000666526 SCV000946429 pathogenic Glycogen storage disease, type II 2018-09-17 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 493 of the GAA protein (p.Pro493Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with reduced α-glucosidase acitivity, findings that are specific for glycogen storage disease type II, also known as Pompe disease (PMID: 24495340). This variant was has been identified in several individuals with adult-onset Pompe disease (PMID: 29181627, 24495340, 25455803, 20033296). ClinVar contains an entry for this variant (Variation ID: 379593). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000666526 SCV000790831 likely pathogenic Glycogen storage disease, type II 2017-04-12 no assertion criteria provided clinical testing

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