ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.8041A>T (p.Met2681Leu) (rs768547151)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182765 SCV000235150 uncertain significance not provided 2019-01-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The M2681L variant has not been published as pathogenic or been reported as benign to our knowledge. It has been observed in one other individual referred for arrhythmia genetic testing at GeneDx, although no segregation data are available. This variant is observed in 6/125002 (0.005%) alleles from individuals of Non-Finnish European ancestry, 1/18660 (0.005%) alleles from individuals of East Asian ancestry, and 1/23660 (0.004%) alleles from individuals of African ancestry, in large population cohorts (Lek et al., 2016). The M2681L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position where amino acids with similar properties to methionine (M) are tolerated across species, and leucine (L) is the wild-type residue at this position in at least one non-mammalian species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, M2681L 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 RCV000470931 SCV000541714 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2016-12-27 criteria provided, single submitter clinical testing This sequence change replaces methionine with leucine at codon 2681 of the RYR2 protein (p.Met2681Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. This variant is present in population databases (rs768547151, ExAC 0.002%) but has not been reported in the literature in individuals with a RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201284). 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 C0"). 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.
Color RCV001189922 SCV001357307 uncertain significance Cardiomyopathy 2019-04-14 criteria provided, single submitter clinical testing

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