Clinical Domain Working Groups

We propose creation of a ClinGen Desmosomal Cardiomyopathy Variant Curation Expert Panel (DesmCMP VCEP) with the aim to optimize the 2015 ACMG/AMP variant classification framework for the PKP2 and DSP genes through disease- and/or gene-informed specifications and strength adjustments of certain rules. PKP2 and DSP were selected as priority genes because (1) both have been shown to be definitive evidence genes for ARVC by the ClinGen ARVC GCEP, (2) heterozygous PKP2 variants are the most commonly identified cause of classical ARVC, detected in up to 60% of genotype-positive index cases in different cohorts and up to 90% of familial cases of ARVC; while DSP variants cause a distinctive form of arrhythmogenic cardiomyopathy that tends to disproportionately involve the left ventricle and is associated with considerable morbidity.