ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.2573C>T (p.Thr858Met) (rs377068202)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics,University of Leuven RCV000768528 SCV000886847 uncertain significance Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678750 SCV000804926 uncertain significance Sudden death 2017-06-16 no assertion criteria provided clinical testing
Color RCV000773287 SCV000906979 uncertain significance Cardiomyopathy 2018-10-26 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the neck and hinge (S2) domain 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 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 13/277178 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Invitae RCV000639095 SCV000760656 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-01-19 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 858 of the RYR2 protein (p.Thr858Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs377068202, ExAC 0.02%). This variant has not been reported in the literature in individuals with RYR2-related disease. 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: "Benign"; Align-GVGD: "Class C15"). 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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