ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1144G>A (p.Val382Met) (rs370057029)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000777719 SCV000913663 uncertain significance Cardiomyopathy 2018-06-26 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the MIR motif 5 of the cytoplasmic MIR 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 this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 19/269552 chromosomes (12/123682 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000202980 SCV000257747 uncertain significance Catecholaminergic polymorphic ventricular tachycardia type 1 2015-06-17 criteria provided, single submitter clinical testing
GeneDx RCV000182675 SCV000235054 uncertain significance not provided 2017-12-14 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The V382M variant has been reported in at least one heterozygous individual from a cohort of patients referred for clinical whole exome sequencing (Landstrom et al., 2017). The V382M variant is observed in 12/123682 (0.01%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The V382M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Invitae RCV000699318 SCV000828023 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-05-31 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 382 of the RYR2 protein (p.Val382Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs370057029, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in the literature in an individual referred for genetic testing (PMID: 28404607). ClinVar contains an entry for this variant (Variation ID: 201209). 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 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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