ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.10528C>A (p.Arg3510Ser) (rs201749277)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769799 SCV000901225 uncertain significance Cardiomyopathy 2017-05-31 criteria provided, single submitter clinical testing
GeneDx RCV000766726 SCV000235172 uncertain significance not provided 2017-09-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The R3510S variant has been reported in at least one heterozygous individual from a cohort of patients referred for clinical whole exome sequencing (Landstrom et al., 2017); however, specific details regarding the indication for genetic testing or the patient's clinical phenotype were not described. This variant has been observed in two other individuals referred for cardiomyopathy genetic testing at GeneDx, although one of these individuals harbored additional cardiogenetic variants, including a pathogenic variant in a different gene, and no segregation data are available for either case observed at GeneDx. Additionally, this variant has been observed 4/66204 (0.006%) alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R3510S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, R3510S is not 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).
Invitae RCV000459970 SCV000541704 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2016-10-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 3510 of the RYR2 protein (p.Arg3510Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs201749277, ExAC 0.006%) but has not been reported in the literature in individuals with a RYR2-related disease. This variant does not occur 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: "Benign"; Align-GVGD: "Class C65"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000182786 SCV000272374 uncertain significance not specified 2015-02-19 criteria provided, single submitter clinical testing The p.Arg3510Ser variant in RYR2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 4/67128 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s201749277). Computational prediction tools and conservation analysis do not pro vide strong support for or against an impact to the protein. In summary, the cli nical significance of the p.Arg3510Ser variant is uncertain.

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