ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1585T>C (p.Ser529Pro)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000799681 SCV000939356 pathogenic Glycogen storage disease, type II 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 529 of the GAA protein (p.Ser529Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with a pathogenic variant (p.Gly483Arg) in GAA in an individual affected with generalized muscle weakness (Invitae). In that individual, this variant was also shown to likely be de novo (Invitae). Manual review of the sequencing data indicated these two variants are on opposite chromosomes (in trans), which suggests the c.1585T>C substitution may contribute to disease. 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Ser529 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 8834250, 19862843, 21471980, 11053688), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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