ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12215C>T (p.Thr4072Met) (rs928224285)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000772023 SCV000904979 uncertain significance Cardiomyopathy 2018-08-28 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic domain of the RYR2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/275082 chromosomes (9/34300 Latino chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000489632 SCV000576527 uncertain significance not provided 2017-04-28 criteria provided, single submitter clinical testing The T4072M variant has not been published as pathogenic or been reported as benign to our knowledge. The T4072M variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T4072M 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, the T4072M variant is located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense mutations occur (Medeiros-Domingo et al., 2009). Nevertheless, though this substitution occurs at a position that is conserved in mammals, M4072 is wild-type in zebrafish. Lastly, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000460637 SCV000541727 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2017-07-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 4072 of the RYR2 protein (p.Thr4072Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. 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. ClinVar contains an entry for this variant (Variation ID: 404238). 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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