ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.10523T>C (p.Ile3508Thr) (rs115622575)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182785 SCV000235171 uncertain significance not provided 2017-09-13 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The I3508T variant has been previously reported in one 57 year-old Spanish male with HCM (Mademont-Soler et al., 2017), and has been observed in two individuals referred for arrhythmia/cardiomyopathy genetic testing at GeneDx. However, no segregation data are available for the published case, or the cases observed at GeneDx. The I3508T variant has also been described in at least one heterozygous individual from a cohort of patients referred for clinical whole exome sequencing (Landstrom et al., 2017); however, specific details regarding the indication for genetic testing or the patient's clinical phenotype were not described. Additionally, I3508T has been observed in 2/9692 (0.021%) alleles from individuals of African ancestry, and 2/66236 (0.003%) alleles from individuals of Non-Finnish European ancestry, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although I3508T 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, this substitution occurs at a position that is not conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, I3508T is not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009).
Invitae RCV000802226 SCV000942048 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-10-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 3508 of the RYR2 protein (p.Ile3508Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs115622575, ExAC 0.02%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201301). 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 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 RCV001179064 SCV001343646 uncertain significance Cardiomyopathy 2019-12-29 criteria provided, single submitter clinical testing

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