Table 1.

Genes Associated with Arrhythmogenic Right Ventricular Cardiomyopathy (ClinGen Gene Validity Classifications: Definitive and Moderate)

Gene 1% of ARVC Caused by Pathogenic Variants in Gene 2

ClinGen Gene Validity Classification

CommentSelected Allelic DisordersOMIM Gene Entry
PKP2 34%-74%DefinitiveMay be more likely to cause VT [Bao et al 2013] Brugada syndrome 602861
DSG2 5%-26%DefinitiveFounder variant in population from East Asia 3 DCM 125671
DSP 2%-39%Definitive 4 DCM 125647
DSC2 1%-2%Definitive 6
  • ARVC can be nonsyndromic or assoc w/mild palmoplantar keratoderma & woolly hair.
  • Founder variant in Hutterite population 7
JUP 0.5%-2%See footnote 8.
  • Heterozygous variant causes nonsyndromic ARVC.
  • Biallelic variants cause Naxos disease (ARVC w/palmoplantar keratoderma & peculiar woolly hair).
TMEM43 RareDefinitive 9Founder variant in population from Newfoundland, Canada 10Auditory neuropathy; TMEM43-related myopathies 612048
DES RareModerateFounder variant in Dutch population 11DCM; conduction system disease; myofibrillar myopathy; Kaiser-type neurogenic scapuloperoneal syndrome 125660
PLN RareModerateDCM; HCM 172405
Unknown 12~40%

ARVC = arrhythmogenic right ventricular cardiomyopathy; DCM = dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy; LV = left ventricle; RV = right ventricle; VT = ventricular tachycardia


Genes are organized first by strength of ClinGen classification, then frequency of causation of ARVC, and then alphabetically.


See Bao et al [2013], Rigato et al [2013], Groeneweg et al [2015], Lazzarini et al [2015], and James et al [2021]. The proportion of ARVC attributed to specific genes varied by cohort studied, suggesting that the relative contribution of the different genes associated with ARVC may differ based on ethnicity and also on the medical care setting at the time of diagnosis (since the criteria for diagnosis of ARVC and for genetic testing may differ).


Homozygosity for DSG2 variant c.1592T>G (p.Phe531Cys) was identified in 8/18 individuals studied and allele frequency was 0.12% in the East Asian population [Chen et al 2019].


Truncating variants in DSP have also been identified in individuals with a myocarditis phenotype (delayed enhancement on cardiac MRI, increased FDG uptake on FDG-PET, and biopsy findings of myocarditis) and sarcoidosis-like phenotype [Smith et al 2020, Ammirati et al 2022, Lota et al 2022].


DSC2 variant c.1660C>T (p.Gln554Ter) is a founder variant in the Hutterite population; homozygosity for p.Gln554Ter is associated with early-onset ARVC [Wong et al 2014].


ClinGen includes JUP as having "Clinical Actionability" for ARVC but does not provide the gene-disease validity classification (see https://search​.clinicalgenome​.org/kb/genes/HGNC:6207).


TMEM43 variant c.1073C>T (p.Ser358Leu) is a highly penetrant founder variant in the Newfoundland, Canada, population characterized by left ventricular involvement and higher risk for sudden cardiac death [Dominguez et al 2020].


DES variant c.38C>T (p.Ser13Phe) is a Dutch founder variant that confers variable expression with right ventricular involvement that is consistent with ARVC but also conduction system disease, which is less common with ARVC [van Tintelen et al 2009].


From: Arrhythmogenic Right Ventricular Cardiomyopathy Overview

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