Long QT syndrome: genes and variants

Genes linked to Long QT syndrome

• KCNQ1: Potassium voltage-gated channel subfamily KQT member 1

  The protein forms the pore of a voltage-gated potassium channel that helps set electrical activity in heart muscle. Its partnerships with KCNE subunits also support normal function in the inner ear and other tissues, while KCNQ1 variants are linked to long-QT and short-QT syndromes.

  175 disease-causing and 468 uncertain variants in KCNQ1 are linked to Long QT syndrome.

• KCNH2: Voltage-gated inwardly rectifying potassium channel KCNH2

  Its unusually rapid inactivation and slow deactivation shape the rapid delayed-rectifier current IKr, a major determinant of ventricular repolarization. Loss-of-function variants can prolong repolarization and cause long-QT syndrome, whereas gain-of-function variants can cause short-QT syndrome.

  114 disease-causing and 1,042 uncertain variants in KCNH2 are linked to Long QT syndrome.

• CALM2: Calmodulin-2

  It supplies an identical calmodulin protein that couples changes in intracellular calcium to numerous signaling and ion-channel targets. Pathogenic missense variants can cause calmodulinopathy with malignant ventricular arrhythmias, including long-QT syndrome and catecholaminergic polymorphic ventricular tachycardia.

  21 disease-causing and 20 uncertain variants in CALM2 are linked to Long QT syndrome.

• SCN5A: Sodium channel protein type 5 subunit alpha

  Its rapid inward sodium current drives the upstroke of the cardiac action potential and enables fast electrical conduction through atrial, ventricular, and conduction-system tissue. Pathogenic variants can cause long-QT syndrome type 3, Brugada syndrome, conduction disease, and overlapping arrhythmia phenotypes.

  16 disease-causing and 36 uncertain variants in SCN5A are linked to Long QT syndrome.

• 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.

  13 disease-causing and 10 uncertain variants in CALM1 are linked to Long QT syndrome.

• CACNA1C: Voltage-dependent L-type calcium channel subunit alpha-1C

  Its opening provides a major source of depolarization-triggered calcium entry in cardiomyocytes, smooth muscle, and neurons, coupling electrical activity to contraction and signaling. Pathogenic variants can cause Timothy syndrome, Brugada or long-QT phenotypes, and several neurodevelopmental disorders.

  12 disease-causing and 20 uncertain variants in CACNA1C are linked to Long QT syndrome.

• CALM3: Calmodulin-3

  It produces the same highly conserved calmodulin protein as CALM1 and CALM2, allowing calcium-dependent regulation of many cardiac and neuronal proteins. Pathogenic missense variants can cause severe inherited arrhythmia syndromes collectively termed calmodulinopathies.

  8 disease-causing and 19 uncertain variants in CALM3 are linked to Long QT syndrome.

• KCNJ5: G protein-activated inward rectifier potassium channel 4

  It contributes to G-protein-activated inward-rectifier potassium current in the heart and endocrine tissues, helping regulate pacemaker activity and membrane potential. Somatic selectivity-altering variants are a common cause of aldosterone-producing adrenal adenomas, while germline variants can cause familial hyperaldosteronism.

  3 disease-causing and 145 uncertain variants in KCNJ5 are linked to Long QT syndrome.

• ANK2: Ankyrin-2

  It organizes membrane proteins and ion-handling complexes by linking them to the cytoskeleton, with especially important roles in cardiomyocytes and neurons. Pathogenic variants can disrupt cardiac electrical organization and cause ankyrin-B syndrome, including sinus-node dysfunction, arrhythmias, and variable QT abnormalities.

  3 disease-causing and 1,434 uncertain variants in ANK2 are linked to Long QT syndrome.

• KCNJ2: Inward rectifier potassium channel 2

  Its inward-rectifier current stabilizes the resting membrane potential in cardiac and skeletal muscle and contributes to terminal cardiac repolarization. Loss-of-function variants cause Andersen-Tawil syndrome, while gain-of-function variants can cause short-QT syndrome.

  0 disease-causing and 2 uncertain variants in KCNJ2 are linked to Long QT syndrome.

Weakly linked (only a few uncertain records): MYBPC3, RBM20, RYR2, CACNA1D, JUP, LDB3, MYH6, MYH7 and 18 more.

Where Long QT syndrome variants cluster

• KCNQ1 Segment H5 (positions 300–320): 30 of 175 disease-causing changes, 5.5× more than its size predicts.
• KCNH2 Segment H5 (positions 612–632): 16 of 114 disease-causing changes, 7.8× more than its size predicts.
• KCNH2 Extracellular (positions 569–611): 21 of 114 disease-causing changes, 5.0× more than its size predicts.
• CALM2 Necessary and sufficient for interaction with PC (positions 77–149): 21 of 21 disease-causing changes, 2.0× more than its size predicts.
• KCNH2 Segment S5 (positions 548–568): 11 of 114 disease-causing changes, 5.3× more than its size predicts.

Known disease-causing variants in Long QT syndrome

Showing 60 of 365.

Uncertain variants in Long QT syndrome that look disease-causing

Which prediction tools work for Long QT syndrome

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

• ESM1b (LLR): 97 out of 100
• MutPred2: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 95 out of 100
• EVE: 94 out of 100
• AlphaGenome (regulatory): 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 89 out of 100
• PolyPhen-2: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 86 out of 100
• phyloP: 74 out of 100
• DMS / MaveDB: 66 out of 100
• AlphaGenome (splicing): 66 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Cardiac arrhythmia is also caused by KCNQ1 variants; they fall in the same places as the Long QT syndrome variants (49 disease-causing).
• Atrial fibrillation, familial, 10 is also caused by KCNQ1 variants; they fall in the same places as the Long QT syndrome variants (8 disease-causing).
• Cardiac arrhythmia is also caused by KCNH2 variants; they fall in the same places as the Long QT syndrome variants (15 disease-causing).
• Short QT syndrome type 3 is also caused by KCNH2 variants; they fall partly in the same places as the Long QT syndrome variants (4 disease-causing).
• Brugada syndrome is also caused by SCN5A variants; they fall mostly in different places as the Long QT syndrome variants (24 disease-causing).
• Cardiac arrhythmia is also caused by SCN5A variants; they fall mostly in different places as the Long QT syndrome variants (17 disease-causing).
• Progressive familial heart block is also caused by SCN5A variants; they fall mostly in different places as the Long QT syndrome variants (4 disease-causing).
• Atrial fibrillation, familial, 10 is also caused by SCN5A variants; they fall mostly in different places as the Long QT syndrome variants (3 disease-causing).

Diseases related to Long QT syndrome

• Cardiac arrhythmia, also linked to ANK2, CACNA1C, KCNH2, KCNJ2 and 2 more
• Brugada syndrome, also linked to ANK2, CACNA1C and SCN5A
• Short QT syndrome type 3, also linked to KCNH2, KCNJ2 and KCNQ1
• Epilepsy, also linked to CACNA1C, KCNQ1 and SCN5A
• Atrial fibrillation, familial, 10, also linked to KCNJ2, KCNQ1 and SCN5A
• Diabetes mellitus, also linked to CACNA1C and KCNQ1
• Sudden infant death syndrome, also linked to CALM2 and SCN5A
• Hypertrophic cardiomyopathy, also linked to ANK2
• Dilated cardiomyopathy, also linked to SCN5A
• Catecholaminergic polymorphic ventricular tachycardia, also linked to CALM1
• Primary dilated cardiomyopathy, also linked to SCN5A
• Type 2 diabetes mellitus, also linked to KCNQ1

Frequently asked questions

Which genes are linked to Long QT syndrome?

In CATVariant, Long QT syndrome is linked to 10 analyzed proteins: KCNQ1 (Potassium voltage-gated channel subfamily KQT member 1), KCNH2 (Voltage-gated inwardly rectifying potassium channel KCNH2), CALM2 (Calmodulin-2), SCN5A (Sodium channel protein type 5 subunit alpha), CALM1 (Calmodulin-1), CACNA1C (Voltage-dependent L-type calcium channel subunit alpha-1C) and 4 more.

How many genetic variants are linked to Long QT syndrome?

3,934 variants: 365 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 3,230 are of uncertain significance or have conflicting reports.

Which uncertain variants in Long QT syndrome look disease-causing?

22 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example KCNQ1 W305L, KCNQ1 R562M, KCNQ1 T322K, KCNH2 R823Q and KCNQ1 A344T. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Long QT syndrome?

Among tools not trained on clinical labels, ESM1b (LLR) separates this disease's known disease-causing variants from harmless ones best (AUROC 0.97, based on 191 disease-causing and 74 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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