ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.14600T>C (p.Ile4867Thr) (rs1064796516)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486020 SCV000573315 likely pathogenic not provided 2018-05-14 criteria provided, single submitter clinical testing The I4867T likely pathogenic variant in the RYR2 gene has not been published as pathogenic or been reported as benign to our knowledge. However, I4867T was identified as an apparently de novo variant in another patient with tachycardia referred for genetic testing at GeneDx. I4867T is not observed in large population cohorts (Lek et al., 2016). The I4867T variant 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. Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Other missense variants in the same residue (I4867V, I4867M) have been reported in families with CPVT or polymorphic ventricular tachycardia (Kumar et al., 2013; Priori et al., 2002), and in vitro studies of cells expressing the I4867M variant demonstrated enhanced spontaneous calcium ion release, supporting a gain of function mechanism (Jiang et al., 2005).In summary, I4867T in the RYR2 gene is interpreted as a likely pathogenic variant.

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