ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.10933G>A (p.Ala3645Thr)

dbSNP: rs1558304228
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002547163 SCV000818866 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2018-05-18 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 3645 of the RYR2 protein (p.Ala3645Thr). 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 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 tolerated, 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.
Color Diagnostics, LLC DBA Color Health RCV001183074 SCV001348729 uncertain significance Cardiomyopathy 2019-05-20 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 3645 of the RYR2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. 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 not been identified in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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