ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12917T>C (p.Phe4306Ser) (rs776091285)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182648 SCV000235024 uncertain significance not provided 2018-12-07 criteria provided, single submitter clinical testing The F4306S variantin the RYR2 gene has been identified in one individual with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Akdis et al., 2016), and it has been identified in conjunction with additional cardiogenetic variants in one other individual referred for cardiomyopathy genetic testing at GeneDx. However, thus far, segregation data is limited or absent for this individual. The F4306S variant is observed in 7/111,248 (0.006%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The F4306S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
Invitae RCV000231189 SCV000285695 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-01-09 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 4306 of the RYR2 protein (p.Phe4306Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is present in population databases (rs776091285, ExAC <0.01%). This variant has been reported in the literature in a patient affected with arrythmogenic ventricular dysplasia/cardiomyopathy (PMID: 26569459). ClinVar contains an entry for this variant (Variation ID: 201186). This variant is located in the C-terminal domain of the RYR2 protein, a region where pathogenic variants have been reported to cluster. (PMID: 19926015). However, 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. In addition, the serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. In summary, this variant is a rare missense change that is not predicted to affect protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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