ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1392G>C (p.Arg464Ser) (rs372786811)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497650 SCV000589915 likely pathogenic not provided 2018-08-14 criteria provided, single submitter clinical testing The R464S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R464S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R464S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in nearby residues (D459N, G461S, L462P, V466F) have been reported in the Human Gene Mutation Database in association with Pompe disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000691429 SCV000819207 uncertain significance Glycogen storage disease, type II 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 464 of the GAA protein (p.Arg464Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs372786811, ExAC 0.006%). This variant has not been reported in the literature in individuals with GAA-related disease. ClinVar contains an entry for this variant (Variation ID: 432217). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000691429 SCV000895138 uncertain significance Glycogen storage disease, type II 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000691429 SCV001282568 uncertain significance Glycogen storage disease, type II 2018-02-09 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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