ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12326T>C (p.Met4109Thr) (rs1373714510)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657964 SCV000779735 likely pathogenic not provided 2018-05-31 criteria provided, single submitter clinical testing The M4109T likely pathogenic variant in the RYR2 gene has not been published as pathogenic or reported as benign to our knowledge. The M4109T variant is not observed in large population cohorts (Lek et al., 2016). This variant was apparently de novo in one individual referred for CPVT testing at GeneDx, though identity testing was not performed. In addition, the M4109T 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, M4109T is 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) and another missense variant (M4109R) at the same residue has been reported in association with CPVT (Nof et al., 2011; Itzhaki et al., 2012).
Invitae RCV000639061 SCV000760620 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2017-08-24 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 4109 of the RYR2 protein (p.Met4109Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. 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 disease. This variant occurs 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, 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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