ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.9085A>G (p.Ile3029Val) (rs370141970)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182773 SCV000235159 uncertain significance not provided 2013-01-16 criteria provided, single submitter clinical testing p.Ile3029Val (ATT>GTT): c.9085 A>G in exon 64 of the RYR2 gene (NM_001035.2). The Ile3029Val variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ile3029Val results in a conservative amino acid substitution of one non-polar amino acid with another at a position that is conserved across species. The Ile3029Val variant was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. However, in silico analysis predicts Ile3029Val is benign to the protein structure/function. Also, no mutations in nearby codons have been reported in association with CPVT, and Ile3029Val does not occur in one of the mutation hotspot regions of the RYR2 gene (Medeiros-Domingo A et al., 2009). We cannot definitively determine if Ile3029Val is a disease-causing mutation or a rare benign variant. The variant is found in CPVT panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000393089 SCV000356375 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000314238 SCV000356376 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000393089 SCV000760630 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-09-10 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 3029 of the RYR2 protein (p.Ile3029Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs370141970, ExAC 0.008%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201290). 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 C25"). 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.
Color RCV001192120 SCV001360099 likely benign Cardiomyopathy 2018-11-09 criteria provided, single submitter clinical testing

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