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Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy, which is associated with life-threatening ventricular arrhythmias. Approximately 60% of patients carry a putative disease-causing genetic variant, but interpretation of genetic test results can be challenging. The aims of this study were to systematically reclassify genetic variants in patients with ARVC and to assess the impact on ARVC diagnosis. Methods: This study included patients from the Multicenter Zurich ARVC Registry who hosted a genetic variant deemed to be associated with the disease. Reclassification of pathogenicity was performed according to the modified 2015 American College of Medical Genetics criteria. ARVC diagnosis (categories: definite, borderline, possible) based on the 2010 Task Force Criteria was reclassified after genetic readjudication. Results: In 79 patients bearing 80 unique genetic variants, n=47 (58.8%) genetic variants were reclassified, and reclassification was judged to be clinically relevant in n=33 (41.3%). Variants in plakophilin-2 ( PKP2 ) were shown to reclassify less frequently as compared with other genes ( PKP2 , n=1, 8.3%; desmosomal non- PKP2 , n=20, 66.7%; nondesmosomal, n=26, 68.4%; P =0.001for overall comparison; PKP2 versus desmosomal non- PKP2, P =0.001; PKP2 versus nondesmosomal, P Conclusions: Given that approximately half of genetic variants were reclassified, with 10.1% of patients losing their definite disease status, accurate determination of variant pathogenicity is of utmost importance in the diagnosis of ARVC.

Zusammenfassung. Die arrhythmogene rechtsventrikuläre Kardiomyopathie / Dysplasie beschreibt eine genetische Erkrankung welche zu einer Umwandlung des Herzmuskels in Fett-und Bindegewebe, typischerweise im rechten Ventrikel führt. Biventrikuläre und linksventrikuläre Subtypen stellen zudem klinische Manifestationen dar. Mutationen in desmosomalen und nicht-desmosomalen Proteinen führen zu elektrischer und mechanischer Instabilität welche sich klinisch als initial als Rhythmusstörungen zeigen. Da die Erkrankung insbesondere junge Sportler betrifft, sind die Frühdiagnose und die adäquate Therapie von grosser Bedeutung, da die Erkrankung auch zum plötzlichen Herztod führen kann.