ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.11116G>A (p.Asp3706Asn) (rs942040362)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523159 SCV000618680 uncertain significance not provided 2017-06-29 criteria provided, single submitter clinical testing The D3706N variant of uncertain significance in the RYR2 gene has been reported previously as an incidental finding in a cohort of individuals referred for whole exome sequencing; however, specific clinical information about the individual(s) harboring this variant was not provided (Landstrom et al., 2017). D3706N is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D3706N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Moreover, this substitution occurs at a position that is conserved in mammals. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating that this region of the gene is not known to harbor disease-causing variants.
Color RCV001183827 SCV001349669 uncertain significance Cardiomyopathy 2019-03-30 criteria provided, single submitter clinical testing
Invitae RCV001242085 SCV001415150 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-03-19 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 3706 of the RYR2 protein (p.Asp3706Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 450136). 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 C0"). 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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