ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.629C>T (p.Thr210Ile) (rs371086868)

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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 RCV000590204 SCV000697626 uncertain significance not provided 2016-05-23 criteria provided, single submitter clinical testing Variant summary: The RYR2 c.629C>T (p.Thr210Ile) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/120762 control chromosomes at a frequency of 0.0000083, 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 via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV001239509 SCV001412385 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 210 of the RYR2 protein (p.Thr210Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs371086868, ExAC 0.01%). 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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