Catecholaminergic polymorphic ventricular tachycardia: genes and variants

Genes linked to Catecholaminergic polymorphic ventricular tachycardia

• 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.

  58 disease-causing and 1,574 uncertain variants in RYR2 are linked to Catecholaminergic polymorphic ventricular tachycardia.

• CALM1: Calmodulin-1

  It translates intracellular calcium signals into changes in the activity of ion channels, kinases, phosphatases, and many other targets. De novo missense variants can cause severe calmodulinopathy, particularly long-QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and sudden cardiac arrest.

  11 disease-causing and 10 uncertain variants in CALM1 are linked to Catecholaminergic polymorphic ventricular tachycardia.

• CASQ2: Calsequestrin-2

  It buffers calcium inside the cardiac sarcoplasmic reticulum and helps regulate calcium release through RYR2 during each heartbeat. Biallelic and some dominant pathogenic variants cause catecholaminergic polymorphic ventricular tachycardia by destabilizing intracellular calcium handling.

  7 disease-causing and 181 uncertain variants in CASQ2 are linked to Catecholaminergic polymorphic ventricular tachycardia.

• TRDN: Triadin

  It organizes the sarcoplasmic-reticulum calcium-release complex and helps couple calsequestrin and ryanodine receptors in cardiac and skeletal muscle. Biallelic loss-of-function variants cause triadin knockout syndrome with severe exercise- or stress-triggered ventricular arrhythmias.

  2 disease-causing and 302 uncertain variants in TRDN are linked to Catecholaminergic polymorphic ventricular tachycardia.

Weakly linked (only a few uncertain records): MYBPC3, ANK2, DSP and GABRA1.

Where Catecholaminergic polymorphic ventricular tachycardia variants cluster

• CALM1 Necessary and sufficient for interaction with PC (positions 77–149): 10 of 11 disease-causing changes, 1.9× more than its size predicts.
• RYR2 Cytoplasmic (positions 4871–4967): 5 of 58 disease-causing changes, 4.4× more than its size predicts.
• RYR2 MIR 5 (positions 351–408): 3 of 58 disease-causing changes, 4.4× more than its size predicts.

Known disease-causing variants in Catecholaminergic polymorphic ventricular tachycardia

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Uncertain variants in Catecholaminergic polymorphic ventricular tachycardia that look disease-causing

Which prediction tools work for Catecholaminergic polymorphic ventricular tachycardia

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 89 out of 100
• AlphaMissense: 89 out of 100
• MetaLR: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 87 out of 100
• SIFT: 84 out of 100
• MutPred2: 79 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 77 out of 100

Diseases related to Catecholaminergic polymorphic ventricular tachycardia

• Long QT syndrome, also linked to CALM1
• Arrhythmogenic right ventricular dysplasia, also linked to RYR2
• Arrhythmogenic right ventricular cardiomyopathy, also linked to RYR2
• Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, also linked to RYR2

Frequently asked questions

Which genes are linked to Catecholaminergic polymorphic ventricular tachycardia?

In CATVariant, Catecholaminergic polymorphic ventricular tachycardia is linked to 4 analyzed proteins: RYR2 (Ryanodine receptor 2), CALM1 (Calmodulin-1), CASQ2 (Calsequestrin-2) and TRDN (Triadin).

How many genetic variants are linked to Catecholaminergic polymorphic ventricular tachycardia?

2,329 variants: 78 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 2,071 are of uncertain significance or have conflicting reports.

Which uncertain variants in Catecholaminergic polymorphic ventricular tachycardia look disease-causing?

1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example CASQ2 P308Q. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Catecholaminergic polymorphic ventricular tachycardia?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.89, based on 20 disease-causing and 299 harmless variants).

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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