ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.14000G>T (p.Ser4667Ile) (rs1057523888)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000425522 SCV000533687 uncertain significance not provided 2017-12-01 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The S4667I variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is also not observed in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Additionally, the S4667I variant is located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). Nevertheless, this variant has not been observed in a significant number of affected individuals, and it lacks both large segregation studies and functional evidence which would further clarify its pathogenicity.
Invitae RCV000639110 SCV000760671 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2017-10-19 criteria provided, single submitter clinical testing This sequence change replaces serine with isoleucine at codon 4667 of the RYR2 protein (p.Ser4667Ile). The serine residue is highly conserved and there is a large physicochemical difference between serine and isoleucine. 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. ClinVar contains an entry for this variant (Variation ID: 390770). This variant occurs within one of the three regions of the RYR2 gene (N-terminal domain, central domain, or channel region) where other pathogenic variants have been reported to cluster (PMID: 19926015). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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