ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.3896T>C (p.Ile1299Thr) (rs772551383)

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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 RCV000612033 SCV000713842 uncertain significance not specified 2018-01-22 criteria provided, single submitter clinical testing The p.Ile1299Thr variant in RYR2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 6/24010 African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; rs772 551383). Computational prediction tools and conservation analysis suggest that t he p.Ile1299Thr variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. In summary, the clinical significan ce of the p.Ile1299Thr variant is uncertain. ACMG/AMP Criteria applied: PP3.
Integrated Genetics/Laboratory Corporation of America RCV000612033 SCV000918166 uncertain significance not specified 2018-10-15 criteria provided, single submitter clinical testing Variant summary: RYR2 c.3896T>C (p.Ile1299Thr) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 275658 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3896T>C in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001039611 SCV001203148 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-05-28 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1299 of the RYR2 protein (p.Ile1299Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs772551383, ExAC 0.02%). This variant has not been reported in the literature in individuals with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 506277). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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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