ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.8262G>C (p.Gln2754His) (rs773748242)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182880 SCV000235268 uncertain significance not provided 2014-10-02 criteria provided, single submitter clinical testing p.Gln2754His (CAG>CAC): c.8262 G>C in exon 55 of the RYR2 gene (NM_001035.2). The Q2754H variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The Q2754H variant was not observed in approximately 5,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q2754H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved within mammals. However, in silico analysis predicts this variant likely does not alter the protein structure/function. Missense mutations in nearby residues have not been reported, indicating this region of the protein may tolerate change. This variant does not reside in one of the three mutational hot spots in the RYR2 gene (Medeiros-Domingo et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s).
Invitae RCV000813919 SCV000954303 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-07-23 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 2754 of the RYR2 protein (p.Gln2754His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs773748242, ExAC 0.01%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201390). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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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