ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.616G>A (p.Ala206Thr) (rs930769080)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000780692 SCV000918167 uncertain significance not specified 2018-10-15 criteria provided, single submitter clinical testing Variant summary: RYR2 c.616G>A (p.Ala206Thr) results in a non-conservative amino acid change located in the Inositol 1,4,5-trisphosphate/ryanodine receptor and MIR motif of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246114 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.616G>A in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color RCV001190795 SCV001358379 uncertain significance Cardiomyopathy 2019-05-22 criteria provided, single submitter clinical testing
Invitae RCV001209796 SCV001381246 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-10-18 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 206 of the RYR2 protein (p.Ala206Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 632974). 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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