Short QT syndrome type 3: genes and variants

Genes linked to Short QT syndrome type 3

• 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.

  28 disease-causing and 174 uncertain variants in KCNJ2 are linked to Short QT syndrome type 3.

• 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.

  4 disease-causing and 65 uncertain variants in KCNH2 are linked to Short QT syndrome type 3.

• 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.

  4 disease-causing and 10 uncertain variants in KCNQ1 are linked to Short QT syndrome type 3.

Where Short QT syndrome type 3 variants cluster

• KCNJ2 Selectivity filter (positions 142–147): 5 of 28 disease-causing changes, 12.7× more than its size predicts.

Known disease-causing variants in Short QT syndrome type 3

Uncertain variants in Short QT syndrome type 3 that look disease-causing

Which prediction tools work for Short QT syndrome type 3

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

• AlphaMissense: 100 out of 100
• CATVariant: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 95 out of 100
• SIFT: 94 out of 100
• phyloP: 68 out of 100

Same protein, different disease

• Andersen Tawil syndrome is also caused by KCNJ2 variants; they fall in the same places as the Short QT syndrome type 3 variants (34 disease-causing).
• Long QT syndrome is also caused by KCNH2 variants; they fall mostly in different places as the Short QT syndrome type 3 variants (114 disease-causing).
• Cardiac arrhythmia is also caused by KCNH2 variants; they fall mostly in different places as the Short QT syndrome type 3 variants (15 disease-causing).
• Long QT syndrome is also caused by KCNQ1 variants; they fall mostly in different places as the Short QT syndrome type 3 variants (175 disease-causing).
• Cardiac arrhythmia is also caused by KCNQ1 variants; they fall mostly in different places as the Short QT syndrome type 3 variants (49 disease-causing).
• Atrial fibrillation, familial, 10 is also caused by KCNQ1 variants; they fall mostly in different places as the Short QT syndrome type 3 variants (8 disease-causing).
• Jervell and Lange-Nielsen syndrome is also caused by KCNQ1 variants; they fall mostly in different places as the Short QT syndrome type 3 variants (4 disease-causing).

Diseases related to Short QT syndrome type 3

• Long QT syndrome, also linked to KCNH2, KCNJ2 and KCNQ1
• Cardiac arrhythmia, also linked to KCNH2, KCNJ2 and KCNQ1
• Atrial fibrillation, familial, 10, also linked to KCNJ2 and KCNQ1
• Type 2 diabetes mellitus, also linked to KCNQ1
• Andersen Tawil syndrome, also linked to KCNJ2
• Epilepsy, also linked to KCNQ1
• Monogenic hearing loss, also linked to KCNQ1
• Primary familial hypertrophic cardiomyopathy, also linked to KCNH2
• Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency, also linked to KCNH2
• Diabetes mellitus, also linked to KCNQ1
• Beckwith-Wiedemann syndrome, also linked to KCNQ1
• Jervell and Lange-Nielsen syndrome, also linked to KCNQ1

Frequently asked questions

Which genes are linked to Short QT syndrome type 3?

In CATVariant, Short QT syndrome type 3 is linked to 3 analyzed proteins: KCNJ2 (Inward rectifier potassium channel 2), KCNH2 (Voltage-gated inwardly rectifying potassium channel KCNH2) and KCNQ1 (Potassium voltage-gated channel subfamily KQT member 1).

How many genetic variants are linked to Short QT syndrome type 3?

300 variants: 36 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 249 are of uncertain significance or have conflicting reports.

Which uncertain variants in Short QT syndrome type 3 look disease-causing?

8 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example KCNJ2 M301V, KCNJ2 G144V, KCNJ2 R189K, KCNJ2 M301L and KCNJ2 G146D. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Short QT syndrome type 3?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 1.00, based on 31 disease-causing and 14 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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