Rare RYR2 p.Thr85Ile variant is associated with catecholaminergic polymorphic ventricular tachycardia

Mutations in the cardiac ryanodine receptor 2 gene (RYR2) are noted in approximately 55% of the patients with catecholaminergic polymorphic ventricular tachycardia (CPVT). However, a high background rate of rare amino acid-altering variants in RYR2 [≈3% (whites) to 6% (nonwhites)] in combination with delayed onset and variable expressivity of the CPVT phenotype make attributing causality to rare RYR2 variants difficult. The proposed set of guidelines for characterization of variants include, among many different criteria, functional studies to classify variants as pathogenic versus non- pathogenic. However, in vitro data, especially for complex channelopathies like CPVT, does not always correlate well with the human phenotype; therefore, characterizing the phenotypic features of rare RYR2 variants in humans is of importance. We report a 13-year-old carrier of a rare maternally inherited variant in exon 3 of RYR2 (p.Thr85Ile, c.254C>T [rs772005577]) who was successfully resuscitated from exercise-associated sudden cardiac arrest and was subsequently found to have exercise-induced complex ventricular ectopy. His brother, who has been asymptomatic, was also found to carry the same variant and demonstrated complex ventricular ectopy on exercise stress testing. These findings suggest that this rare variant, which has previously not been reported in patients with RYR2 related conditions, is associated with pathogenicity.