ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1832T>C (p.Leu611Pro) (rs794728726)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182692 SCV000235071 uncertain significance not provided 2016-07-19 criteria provided, single submitter clinical testing The Leu611Pro variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Leu611Pro results in a semi-conservative amino acid substitution of a nonpolar Leucine with a non-polar, sterically constrained Proline at a position that is conserved across species. In silico analysis predicts Leu611Pro is probably damaging to the protein structure/function. The Leu611Pro variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. A mutation in a nearby residue (Ser616Leu) has been reported in association with CPVT, however, Leu611Pro does not occur in or near any of the mutation hotspot regions of the RYR2 gene (Medeiros-Domingo A et al., 2009). With the clinical and molecular information available at this time, we cannot definitively determine if Leu611Pro is a disease-causing mutation or a rare benign variant.
Invitae RCV001056394 SCV001220835 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-12-06 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 611 of the RYR2 protein (p.Leu611Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 201224). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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