ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12859T>C (p.Tyr4287His) (rs190009333)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151774 SCV000200197 uncertain significance not specified 2014-01-22 criteria provided, single submitter clinical testing The Tyr4287His variant in RYR2 has not been previously reported in individuals w ith cardiomyopathy, but has been identified in 1/194 Han Chinese chromosomes by the 1000 Genomes Project (dbSNP rs190009333) and in 1/8238 European American chr omosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS /). Computational analyses (biochemical amino acid properties, conservation, Ali gnGVGD, PolyPhen2, and SIFT) suggest that this variant may impact the protein, t hough this information is not predictive enough to determine pathogenicity. Addi tional information is needed to fully assess the clinical significance of this v ariant.
Invitae RCV000460342 SCV000541684 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2016-06-18 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 4287 of the RYR2 protein (p.Tyr4287His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs190009333, ExAC 0.002%) but has not been reported in the literature in individuals with a RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 165127). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000777991 SCV000914097 uncertain significance Cardiomyopathy 2018-06-11 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the transmembrane domain of the pore-forming region of the RYR2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact 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 this variant been reported in an individual affected with cardiovascular disorders in the literature. This variant has also been identified in 5/276622 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

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