rs397508068 — KCNQ1 Phe340del

KCNQ1 Phe340del — A Silent Channel Fault That Can Stop the Heart

The heart beats reliably because each contraction is followed by a precisely timed electrical reset called cardiac repolarization¹¹ cardiac repolarization
The phase of the cardiac cycle in which the electrical charge of each heart muscle cell returns to its resting state, readying it for the next beat. Normal repolarization takes approximately 350–440 milliseconds, measured as the QT interval on an ECG. The largest contributor to repolarization during exercise is the IKs current, carried by the potassium channel encoded by KCNQ1. When this channel is impaired, repolarization slows, the QT interval lengthens, and the heart becomes vulnerable to a potentially lethal arrhythmia: torsades de pointes²² torsades de pointes
French for "twisting of the points" — a rapid ventricular arrhythmia where the QRS complexes spiral around the ECG baseline. Can degenerate into ventricular fibrillation and cardiac arrest if not terminated spontaneously or by defibrillation.

The rs397508068 variant deletes three nucleotides (CTT) from KCNQ1's coding sequence, removing phenylalanine at position 340 of the protein (p.Phe340del) within the S6 transmembrane helix. This in-frame deletion is classified pathogenic by ClinVar (RCV000045930, allele ID 67598) and linked to Long QT syndrome type 1 (LQT1)³³ Long QT syndrome type 1 (LQT1)
The most common hereditary form of Long QT syndrome, accounting for ~30–35% of all genotyped LQTS cases. LQT1 is caused exclusively by loss-of-function mutations in KCNQ1, Jervell and Lange-Nielsen syndrome (when a second pathogenic KCNQ1 variant is inherited from the other parent), and familial atrial fibrillation.

The Mechanism

Phenylalanine-340 sits within the S6 transmembrane helix — the innermost transmembrane segment that lines the channel pore and forms the activation gate. Deleting this residue disrupts local helical geometry, impairing the voltage- dependent conformational change that opens the channel and reducing IKs current density. Transmembrane domain mutations in KCNQ1 often produce mutant protein that co-assembles with the normal subunit into heteromeric channels, creating dominant-negative effects⁴⁴ dominant-negative effects
When a mutant protein impairs the function of the remaining normal protein by assembling into the same complex. In KCNQ1 tetramers, even a minority of mutant subunits can suppress the entire channel's function — explaining why heterozygous transmembrane mutations can reduce IKs by more than 50%, worse than losing one copy entirely.

The clinical consequence is prolonged QT at rest that worsens markedly during sympathetic activation (exercise, emotional stress, sudden startle). Swimming is the highest-risk activity for LQT1 — it combines intense adrenergic drive with cold-water-triggered vagal tone, stressing the IKs-dependent repolarization reserve from two directions simultaneously.

The Evidence

Moss et al. (Circulation, 2007 — PMID 17470695)⁵⁵ Moss et al. (Circulation, 2007 — PMID 17470695) followed 600 LQT1 patients with 77 different KCNQ1 mutations across three international registries. Transmembrane-domain mutations carried a hazard ratio of 2.06 (P<0.001) for cardiac events compared with C-terminal mutations. Mutations causing dominant-negative dysfunction (>50% IKs reduction) added a further hazard ratio of 2.26 (P<0.001) over haploinsufficiency alone — both independent of sex, QTc, and prior symptoms.

For pharmacological management, Barsheshet et al. (Circulation, 2012 — PMID 22456477)⁶⁶ Barsheshet et al. (Circulation, 2012 — PMID 22456477) showed that beta-blocker therapy reduced life-threatening cardiac events by 88% (HR 0.12; 95% CI 0.02–0.73) in carriers of cytoplasmic loop KCNQ1 mutations, where channel activation fails under beta-adrenergic stimulation. The same treatment was ineffective in other KCNQ1 mutation types (HR 0.82, P=0.68), underscoring the importance of mutation-specific risk management.

Kapa et al. (Circulation, 2009 — PMID 19841300)⁷⁷ Kapa et al. (Circulation, 2009 — PMID 19841300) established that non-missense KCNQ1 variants (including in-frame deletions such as p.Phe340del) have a >99% estimated predictive value for pathogenicity regardless of domain location — setting them apart from missense variants whose pathogenicity requires domain-specific and functional validation.

Practical Actions

LQT1 management rests on three pillars: beta-blocker therapy, avoidance of QT-prolonging drugs, and activity guidance. The CredibleMeds database⁸⁸ CredibleMeds database
Maintained by Arizona CERT and the University of Arizona; freely searchable at crediblemeds.org — classifies QT risk as Known, Conditional, Possible, or Not Associated for hundreds of drugs is the essential reference for medication safety in LQT1. Common high-risk drugs include antiarrhythmics (sotalol, quinidine), antibiotics (azithromycin, fluoroquinolones), antiemetics (ondansetron), antipsychotics (haloperidol, quetiapine), and antimalarials (hydroxychloroquine). Every new prescription must be cross-checked before dispensing.

An inherited arrhythmia specialist should lead risk stratification. The baseline workup includes resting 12-lead ECG, exercise stress test (which unmasks exercise-triggered QT prolongation that may be borderline at rest), and family cascade testing — each first-degree relative has a 50% risk of carrying the variant.

Interactions

KCNQ1 assembles with KCNE1 (MinK) as an obligate beta-subunit. Pathogenic KCNE1 variants cause LQT5 independently; in combination with a KCNQ1 variant, they worsen IKs loss. Biallelic KCNQ1 mutations — inheriting a pathogenic variant from both parents — cause Jervell and Lange-Nielsen syndrome⁹⁹ Jervell and Lange-Nielsen syndrome
Autosomal recessive severe LQT syndrome plus sensorineural deafness. The deafness arises because the IKs channel (KCNQ1/KCNE1) is essential for potassium secretion into cochlear endolymph. JLN carries substantially higher cardiac event rates than heterozygous LQT1 and requires aggressive management including ICD in most cases. Children of an LQT1 carrier whose partner also carries a KCNQ1 variant have a 25% chance of developing JLN — a critical consideration in reproductive counseling.