ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12245A>C (p.Glu4082Ala) (rs1057524762)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000423260 SCV000536412 uncertain significance not provided 2017-01-19 criteria provided, single submitter clinical testing The E4082A variant has not been reported in as pathogenic or benign to our knowledge and is not observed in largepopulation cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). It waspublished in a functional study as part of a triple residue variant (D4079A/E4081A/E4082A) that demonstrated noeffect of the triple residue variant on Ca(2+)-dependent activation or RYR2 expression; however, E4082A was notstudied in isolation and the clinical relevance of this study is unclear. The E4082A variant is a non-conservativeamino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity,charge, size and/or other properties. While this substitution occurs at a position where amino acids with similarproperties to glutamic acid are tolerated across species, A4082 is not the wildtype residue in any of the 99 vertebratespecies for which data is available in the UCSC browser. Furthermore, the E4082A variant is located in one of thethree hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009).
Invitae RCV000540789 SCV000637493 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-09-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 4082 of the RYR2 protein (p.Glu4082Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RYR2-related disease. This variant is located in the second EF-hand Ca2+ binding motif of the RYR2 that has been shown to be required for Ca2+ binding/release. However, the functional relevance of a missense substitution at p.Glu4028 is uncertain. 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 C65"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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