Although RYR2 has a relatively high background rate of rare variants, by setting stringent population frequency thresholds (see the “Methods” section) and identifying enriched clusters, we can identify variant classes with a very high probability of pathogenicity—indeed the EF will be higher still for definitively diagnosed CPVT cases given the relatively low diagnostic yield observed in the referral cohort. The gene discussed is RYR2; the disease is catecholaminergic polymorphic ventricular tachycardia.