ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.2717C>T (p.Pro906Leu) (rs397516522)

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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 RCV000036719 SCV000060374 uncertain significance not specified 2013-05-03 criteria provided, single submitter clinical testing The Pro906Leu variant in RYR2 has been identified by our laboratory in 1 Caucasi an individual with HCM, but was not identified in large population studies. Comp utational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to t he protein. In addition, this variant is located in the last three bases of the exon, which is part of the 5? splice region. Computational tools do not suggest an impact to splicing, though this information is not predictive enough to rule out pathogenicity. In summary, additional information is needed to fully assess the clinical significance of this variant.
Invitae RCV000702859 SCV000831731 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-06-08 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 906 of the RYR2 protein (p.Pro906Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs397516522, ExAC 0.003%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 43760). 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 C65"). 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 RCV000777966 SCV000914067 uncertain significance Cardiomyopathy 2018-10-25 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is located in the cytoplasmic domain of the RYR2 protein. 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 10/276358 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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