ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.3037C>T (p.Arg1013Trp) (rs777740439)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182868 SCV000235256 uncertain significance not provided 2017-08-29 criteria provided, single submitter clinical testing p.Arg1013Trp (CGG>TGG): c.3037 C>T in exon 26 of the RYR2 gene (NM_001035.2). A variant of unknown significance has been identified in the RYR2 gene. The R1013W variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R1013W variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1013W 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. Additionally, this substitution occurs at a position that is class conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense change involving the same residue (R1013Q) has been previously reported in association with CPVT (Medeiros- Domingo A et al., 2009; Tester D et al., 2005). However, R1013Q has been reported with a frequency ranging from 0.1% to 0.8% of alleles in the NHLBI Exome Sequencing Project and 1000 Genomes Project and reported as a variant of unknown significance at GeneDx. Furthermore, R1013W is located in a region of the RYR2 protein that contains few reported mutations and R1013W is not located in any of the three mutation hot spots" in the RYR2 gene (Medeiros-Domingo A et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s)."
Invitae RCV000639109 SCV000760670 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2017-10-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1013 of the RYR2 protein (p.Arg1013Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs777740439, ExAC 0.002%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201379). 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, 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001171190 SCV001333884 uncertain significance Cardiomyopathy 2018-01-02 criteria provided, single submitter clinical testing
Color RCV001171190 SCV001358243 uncertain significance Cardiomyopathy 2020-04-20 criteria provided, single submitter clinical testing

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