ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.11588G>A (p.Gly3863Asp) (rs794728775)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182798 SCV000235184 likely pathogenic not provided 2013-02-06 criteria provided, single submitter clinical testing p.Gly3863Asp (GGC>GAC): c.11588 G>A in exon 86 of the RYR2 gene (NM_001035.2). The Gly3863Asp variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Gly3863Asp results in a non-conservative amino acid substitution of a neutral Glycine with a negatively-charged Aspartic acid at a position that is highly conserved across species. Consequently, in silico analysis predicts Gly3863Asp is damaging to the protein structure/function. Gly3863Asp is located in the channel region, a mutation hotspot region of the RYR2 gene (Medeiros-Domingo A et al., 2009). The Gly3863Asp variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, control data from individuals of other ethnic backgrounds was not available to assess for a population-specific benign polymorphism. In summary, Gly3863Asp is a good candidate for a disease-causing mutation. The variant is found in POSTMORTEM panel(s).
Invitae RCV001221374 SCV001393415 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-05-13 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 3863 of the RYR2 protein (p.Gly3863Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 201313). 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"). 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.

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