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Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited heart-muscle disorder, which is the most common cause of life-threatening arrhythmias and sudden cardiac death (SCD) in young adults and athletes. Early and accurate diagnosis can be crucial in effective ARVC management and prevention of SCD.The genome Aggregation Database (gnomAD) population of 138,632 unrelated individuals was searched for previously identified ARVC variants, classified as pathogenic or unknown on the disease genetic variant database ( http://www.arvcdatabase.info/ ), in five most-commonly mutated genes: PKP2, DSP, DSG2, DSC2 and JUP, where variants account for 40-50% of all the ARVC cases. Minor allele frequency (MAF) of 0.001 was used to define variants as rare or common.The gnomAD data contained 117/364 (32%) of the previously reported pathogenic and 152/266 (57%) of the unknown ARVC variants. The cross-ethnic analysis of MAF revealed that 11 previously classified pathogenic and 57 unknown variants were common (MAF ≥ 0.001) in at least one ethnic gnomAD population and therefore unlikely to be ARVC causing.After applying our MAF analysis the overall frequency of pathogenic ARVC variants in gnomAD was one in 257 individuals, but a more stringent cut-off (MAF ≥ 0.0001) gave a frequency of one in 845, closer to the estimated phenotypic frequency of the disease.Our study demonstrates that the analysis of large cross-ethnic population sequencing data can significantly improve disease variant interpretation. Higher than expected frequency of ARVC variants suggests that a proportion of ARVC-causing variants may be inaccurately classified, implying reduced penetrance of some variants, and/or a polygenic aetiology of ARVC.

Frequency of genetic variants associated with arrhythmogenic right ventricular cardiomyopathy in the genome aggregation database