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Catecholaminergic Polymorphic Ventricular Tachycardia ( CPVT) is a highly lethal cardiac arrhythmia disease occurring during exercise or psychological stress. CPVT has an estimated prevalence of 1:10,000 and has mainly been associated with variants in calcium-regulating genes. Identification of potential false-positive pathogenic variants was conducted by searching the Exome Aggregation Consortium ( ExAC) database ( n = 60,706) for variants reported to be associated with CPVT. The pathogenicity of the interrogated variants was assessed using guidelines from the American College of Medical Genetics and Genomics ( ACMG) and in silico prediction tools. Of 246 variants 38 (15%) variants previously associated with CPVT were identified in the ExAC database. We predicted the CPVT prevalence to be 1:132. The ACMG standards classified 29% of ExAC variants as pathogenic or likely pathogenic. The in silico predictions showed a reduced probability of disease-causing effect for the variants identified in the exome database (p < 0.001). We have observed a large overrepresentation of previously CPVT-associated variants in a large exome database. Based on the frequency of CPVT in the general population, it is less likely that the previously proposed variants are associated with a highly penetrant monogenic form of the disease. [ABSTRACT FROM AUTHOR]