ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.36G>C (p.Gln12His) (rs746811389)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000639033 SCV000760591 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 12 of the RYR2 protein (p.Gln12His). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and histidine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 532322). 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"). 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.
Color RCV000773022 SCV000906404 uncertain significance Cardiomyopathy 2018-06-05 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the N-terminal cytoplasmic domain of the RYR2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has the variant been reported in individuals affected with cardiovascular disease in the literature. This variant is present in the general population (3/20050 European chromosomes in the Genome Aggregation Database, gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

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