ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.13130C>T (p.Ser4377Leu)

dbSNP: rs869025514
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208101 SCV000264192 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2015-07-27 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000771881 SCV000904638 uncertain significance Cardiomyopathy 2023-07-26 criteria provided, single submitter clinical testing This missense variant replaces serine with leucine at codon 4377 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 1/248466 chromosomes 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.
Invitae RCV002517405 SCV002256506 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 4377 of the RYR2 protein (p.Ser4377Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 222795). 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. 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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