ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.836C>T (p.Thr279Met) (rs754312807)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000588776 SCV000697631 uncertain significance not provided 2017-05-30 criteria provided, single submitter clinical testing Variant summary: The RYR2 c.836C>T (p.Thr279Met) variant involves the alteration of a conserved nucleotide, is located in MIR motif (InterPro, UniProt) and is predicted to be damaging by 3/4 in silico tools (SNPsandGO not captured due to low reliability index). This variant was found in 1/119600 control chromosomes from ExAC at a frequency of 0.0000084, which does not exceed the estimated maximal expected allele frequency of a pathogenic RYR2 variant (0.000055). The variant of interest has not, to our knowledge, been reported in affected individuals with cardiac phenotypes via publications and/or reputable databases/clinical diagnostic laboratories, nor has it been evaluated for functional impact by in vivo/vitro studies. In COSMIC, this variant is reported as somatic variant in one carcinoma sample from large intestine. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000688340 SCV000815946 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-05-10 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 279 of the RYR2 protein (p.Thr279Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs754312807, ExAC 0.002%). 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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