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

dbSNP: rs1057523888

Total submissions: 2

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	RCV002525464	SCV000760671	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2017-10-10	criteria provided, single submitter	clinical testing	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). 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 is not present in population databases (ExAC no frequency). 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.