Abstract 19585: Overestimation of Functional Cardiomyopathy Disease Variants in the Human Gene Mutation Database

Introduction: Dilated cardiomyopathy (DM), hypertrophic cardiomyopathy (HCM), and arryhmogenic right ventricular dysplasia (ARVD) have been associated with germline genetic variants. However, uncertainty exists regarding the functional impact of specific variants described in the literature. Hypothesis: We hypothesized that a substantial fraction of presumed casual variants would be identified as non-disease causing in a normal patient population. Methods: Missense variants associated with three main subtypes of cardiomyopathy were extracted from Human Gene Mutation Database Professional (HGMD). To assess the prevalence and pathogenicity of these potential disease-causing alleles, the population frequency of each variant was screened in a recently published large-scale exome database of over 60,000 whole exomes (ExAC). In addition, PolyPhen-2 was used to predict the functional impact of amino acid substitution for each missense variant. Results: In the HGMD, 1,405 missense variants were associated with ca...