ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.13067C>T (p.Ala4356Val)

dbSNP: rs981875785
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002538129 SCV000953069 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2018-07-11 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with RYR2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 4356 of the RYR2 protein (p.Ala4356Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine.
Color Diagnostics, LLC DBA Color Health RCV001525406 SCV001735496 uncertain significance Cardiomyopathy 2020-10-19 criteria provided, single submitter clinical testing This missense variant replaces alanine with valine at codon 4356 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not 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). The 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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