BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a 
lethal, rare hereditary disease with an estimated prevalence of 1:10 000. The 
genetic variants that cause CPVT are usually highly penetrant. To date, about 
189 variants in 5 genes (RYR2, CASQ2, CALM1, TRND, and KCNJ2) have been 
associated with CPVT pathogenesis.
METHODS AND RESULTS: The Exome Sequencing Project database (ESP; n=6503) was 
systematically searched for previously published missense and nonsense 
CPVT-associated variants reported in several comprehensive reviews and in 2 
databases: The Human Gene Mutation Database and The Inherited Arrhythmias 
Database. We used 4 different prediction tools to assess all missense variants 
previously associated with CPVT and compared the prediction of protein damage 
between CPVT-associated variants identified in the ESP and those variants not 
identified in the ESP. We identified 11% of the variants previously associated 
with CPVT in the ESP population. In the literature, 57% of these variants were 
reported as novel disease-causing variants absent in the healthy control 
subjects. These putative CPVT variants were identified in 41 out of 6131 
subjects in the ESP population, corresponding to a prevalence of CPVT of up to 
1:150. Using an agreement of ≥3, in silico prediction tools showed a 
significantly higher frequency of damaging variants among the CPVT-associated 
variants not identified in the ESP database (83%) compared with those variants 
identified in the ESP (50%; P=0.021).
CONCLUSIONS: We identified a substantial overrepresentation of CPVT-associated 
variants in a large exome database, suggesting that these variants are not 
necessarily the monogenic cause of CPVT.