ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.8147A>T (p.Lys2716Ile) (rs749618476)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724224 SCV000231340 uncertain significance not provided 2014-11-15 criteria provided, single submitter clinical testing
Invitae RCV000233218 SCV000285750 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-10-17 criteria provided, single submitter clinical testing This sequence change replaces lysine with isoleucine at codon 2716 of the RYR2 protein (p.Lys2716Ile). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and isoleucine. This variant is present in population databases (rs749618476, ExAC 0.01%). This variant has not been reported in the literature in individuals with a RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 197961). 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 (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, this variant has uncertain impact on RYR2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000724224 SCV000576742 uncertain significance not provided 2017-04-20 criteria provided, single submitter clinical testing The K2716I variant in the RYR2 has been reported as an incidental finding from a cohort undergoing whole exomesequencing; authors classified K2716I as a variant of uncertain significance and did not provide patient-specific clinicaldata (Landstrom et al., 2017). The K2716Ivariant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as theseresidues differ in polarity, charge, size and/or other properties. Moreover, this substitution occurs at a position that isconserved across species, and in silico analysis predicts this variant is probably damaging to the proteinstructure/function. Furthermore, the K2716I variant is not observed at a significant frequency in large populationcohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Nonetheless, K2716I isnot located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic variants occur(Medeiros-Domingo et al., 2009).
CeGaT Praxis fuer Humangenetik Tuebingen RCV000724224 SCV001147765 uncertain significance not provided 2019-05-01 criteria provided, single submitter clinical testing
Color RCV001176808 SCV001340866 uncertain significance Cardiomyopathy 2019-11-24 criteria provided, single submitter clinical testing

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