Arrhythmogenic right ventricular cardiomyopathy: genes and variants

Genes linked to Arrhythmogenic right ventricular cardiomyopathy

• PKP2: Plakophilin-2

  It organizes cardiac desmosomes and helps maintain both mechanical adhesion and electrical coupling between cardiomyocytes. Pathogenic variants are a major cause of arrhythmogenic cardiomyopathy and increase susceptibility to ventricular arrhythmias and sudden cardiac death.

  2 disease-causing and 124 uncertain variants in PKP2 are linked to Arrhythmogenic right ventricular cardiomyopathy.

• RYR2: Ryanodine receptor 2

  It releases calcium from the cardiac sarcoplasmic reticulum in response to trigger calcium entering during each action potential, thereby initiating contraction. Pathogenic variants can destabilize calcium release and are a major cause of catecholaminergic polymorphic ventricular tachycardia.

  1 disease-causing and 11 uncertain variants in RYR2 are linked to Arrhythmogenic right ventricular cardiomyopathy.

• DSP: Desmoplakin

  It anchors intermediate filaments to desmosomes, allowing mechanically stressed tissues such as myocardium and epidermis to maintain strong cell-cell adhesion. Pathogenic variants can cause arrhythmogenic or dilated cardiomyopathy and a range of cardiocutaneous disorders.

  1 disease-causing and 8 uncertain variants in DSP are linked to Arrhythmogenic right ventricular cardiomyopathy.

• DSC2: Desmocollin-2

  Its desmosomal adhesion helps cardiomyocytes remain mechanically coupled during repeated contraction. Pathogenic variants can weaken cardiac junctions and contribute to arrhythmogenic cardiomyopathy.

  0 disease-causing and 7 uncertain variants in DSC2 are linked to Arrhythmogenic right ventricular cardiomyopathy.

• DES: Desmin

  Its desmin filaments mechanically integrate sarcomeres with the nucleus, mitochondria, and cell junctions in striated muscle. Pathogenic variants cause desmin-related myopathy and can produce cardiomyopathy, conduction disease, and skeletal-muscle weakness.

  0 disease-causing and 1 uncertain variants in DES are linked to Arrhythmogenic right ventricular cardiomyopathy.

• MYH7: Myosin-7

  Its beta-myosin motor converts ATP hydrolysis into force within cardiac and slow-skeletal-muscle sarcomeres. Pathogenic variants are major causes of hypertrophic and dilated cardiomyopathy and can also produce inherited skeletal myopathies.

  1 disease-causing and 0 uncertain variants in MYH7 are linked to Arrhythmogenic right ventricular cardiomyopathy.

Weakly linked (only a few uncertain records): CDH2, JUP, RYR1, SCN5A, ACTN2, CACNB2, FLNC, MYH6 and 4 more.

Known disease-causing variants in Arrhythmogenic right ventricular cardiomyopathy

Same protein, different disease

• Catecholaminergic polymorphic ventricular tachycardia is also caused by RYR2 variants; they fall mostly in different places as the Arrhythmogenic right ventricular cardiomyopathy variants (58 disease-causing).
• Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome is also caused by RYR2 variants; they fall mostly in different places as the Arrhythmogenic right ventricular cardiomyopathy variants (4 disease-causing).
• Arrhythmogenic right ventricular dysplasia is also caused by RYR2 variants; they fall mostly in different places as the Arrhythmogenic right ventricular cardiomyopathy variants (3 disease-causing).
• Arrhythmogenic right ventricular dysplasia is also caused by DSP variants; they fall mostly in different places as the Arrhythmogenic right ventricular cardiomyopathy variants (6 disease-causing).
• Arrhythmogenic cardiomyopathy with wooly hair and keratoderma is also caused by DSP variants; they fall mostly in different places as the Arrhythmogenic right ventricular cardiomyopathy variants (6 disease-causing).
• Hypertrophic cardiomyopathy is also caused by MYH7 variants; they fall mostly in different places as the Arrhythmogenic right ventricular cardiomyopathy variants (239 disease-causing).
• Dilated cardiomyopathy is also caused by MYH7 variants; they fall mostly in different places as the Arrhythmogenic right ventricular cardiomyopathy variants (21 disease-causing).
• Primary dilated cardiomyopathy is also caused by MYH7 variants; they fall mostly in different places as the Arrhythmogenic right ventricular cardiomyopathy variants (15 disease-causing).
• Myosin storage myopathy is also caused by MYH7 variants; they fall mostly in different places as the Arrhythmogenic right ventricular cardiomyopathy variants (13 disease-causing).
• MYH7-related skeletal myopathy is also caused by MYH7 variants; they fall mostly in different places as the Arrhythmogenic right ventricular cardiomyopathy variants (7 disease-causing).

Diseases related to Arrhythmogenic right ventricular cardiomyopathy

• Arrhythmogenic right ventricular dysplasia, also linked to DSC2, DSP, PKP2 and RYR2
• Dilated cardiomyopathy, also linked to DES, DSP and MYH7
• Familial isolated arrhythmogenic right ventricular dysplasia, also linked to DSC2, DSP and PKP2
• Hypertrophic cardiomyopathy, also linked to DSP and MYH7
• Primary dilated cardiomyopathy, also linked to DES and MYH7
• Primary familial dilated cardiomyopathy, also linked to DES and MYH7
• Familial isolated dilated cardiomyopathy, also linked to DES and MYH7
• Cardiac arrhythmia, also linked to DSP
• Catecholaminergic polymorphic ventricular tachycardia, also linked to RYR2
• Desmin-related myofibrillar myopathy, also linked to DES
• Primary familial hypertrophic cardiomyopathy, also linked to MYH7
• Idiopathic pulmonary fibrosis, also linked to DSP

Frequently asked questions

Which genes are linked to Arrhythmogenic right ventricular cardiomyopathy?

In CATVariant, Arrhythmogenic right ventricular cardiomyopathy is linked to 6 analyzed proteins: PKP2 (Plakophilin-2), RYR2 (Ryanodine receptor 2), DSP (Desmoplakin), DSC2 (Desmocollin-2), DES (Desmin) and MYH7 (Myosin-7).

How many genetic variants are linked to Arrhythmogenic right ventricular cardiomyopathy?

183 variants: 5 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 163 are of uncertain significance or have conflicting reports.

Which uncertain variants in Arrhythmogenic right ventricular cardiomyopathy look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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