ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.3484G>A (p.Val1162Met) (rs377030538)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000590956 SCV000700128 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2016-10-01 criteria provided, single submitter research Found in patient having exome sequencing for an unrelated indication. No known history of arrhythmogenic right ventricular dysplasia. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Color RCV000772100 SCV000905136 uncertain significance Cardiomyopathy 2018-10-27 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic SPRY domain 2 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 RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/246124 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Invitae RCV000541268 SCV000637556 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2017-06-09 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 1162 of the RYR2 protein (p.Val1162Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a RYR2-related disease. This variant does not occur within one of the three regions of the RYR2 gene (N-terminal domain, central domain, or channel region) where other pathogenic variants have been reported to cluster (PMID: 19926015). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on RYR2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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