rs397508077 — KCNQ1 Long QT Type 1 Variant 4 (c.1124_1127del)

Pathogenic 4bp frameshift deletion in KCNQ1 that eliminates the IKs potassium channel's C-terminal domain, causing autosomal dominant Long QT syndrome type 1 with characteristic exercise- and swimming-triggered cardiac events

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KCNQ1 c.1124_1127del — A Broken Cardiac Repolarization Switch

Every heartbeat ends with a brief electrical shutdown: potassium ions rush out of heart muscle cells, repolarizing the membrane and preparing for the next beat. The gene KCNQ1 encodes the pore-forming subunit of the IKs channel11 IKs channel
The slow delayed rectifier potassium current; one of the primary repolarizing currents in ventricular myocytes; encoded by KCNQ1 (alpha subunit) and KCNE1 (beta subunit), which carries much of this repolarizing current. The c.1124_1127del variant (rs397508077) deletes four nucleotides from exon 8 of KCNQ1, frameshifting the protein at isoleucine 375 and eliminating the channel's entire C-terminal assembly domain. The result is haploinsufficiency — one functional KCNQ1 allele instead of two — and a QT interval that cannot reliably shorten during exercise when IKs current is most needed. This is Long QT syndrome type 1 (LQT1), the most common form of congenital LQTS, caused by KCNQ1 loss-of-function mutations in approximately 30–35% of all LQTS cases22 30–35% of all LQTS cases
GeneReviews, NCBI Bookshelf NBK1129, 2024.

The Mechanism

The c.1124_1127del deletion shifts the KCNQ1 reading frame at codon 375 (Ile375), creating a premature stop signal that destroys the C-terminal tetramerization and calmodulin-binding domains of the channel protein. Without the C-terminus33 Without the C-terminus
The C-terminal coiled-coil domain is required for alpha-subunit assembly into functional tetramers; truncation mutants fail to traffic to the membrane and undergo proteasomal degradation, the truncated protein is degraded rather than incorporated into functional channels. The result is haploinsufficiency: the wild-type allele produces roughly half the normal IKs current. Unlike dominant-negative mutations (which actively poison co-assembled channels), haploinsufficiency mutations tend to produce intermediate phenotypic severity — still clinically significant, but less severe on average than transmembrane dominant-negative variants.

During exercise, IKs current normally increases substantially to accelerate repolarization and protect against tachycardia-induced arrhythmia. With only ~50% of normal IKs current available, the QT interval fails to shorten appropriately as heart rate rises. This is why exercise — and swimming in particular, which combines intense sympathetic activation with sudden face-submersion vagal reflexes — produces the highest arrhythmia risk in LQT1, in contrast to LQT2 (auditory triggers) and LQT3 (rest/sleep).

The Evidence

ClinVar classifies this variant as Pathogenic with four-star review status44 Pathogenic with four-star review status
VCV000052962.30; 13 submitting laboratories including GeneDx, Labcorp Genetics, Color Diagnostics, and Ambry Genetics; "criteria provided, multiple submitters, no conflicts". The variant has been identified in multiple unrelated families with LQT syndrome and documented cardiac events including syncope and sudden cardiac death. Population frequency in gnomAD exomes is approximately 4 per million alleles — consistent with a highly penetrant pathogenic variant under strong negative selection.

Moss et al. (Circulation, 2007)55 Moss et al. (Circulation, 2007)
600 KCNQ1 mutation carriers from three international LQTS registries; PMID 17470695 established that KCNQ1 mutations with dominant-negative ion channel effects carry a 2.26-fold greater hazard for cardiac events compared to haploinsufficiency mutations. Frameshift deletions like c.1124_1127del produce haploinsufficiency — placing this variant in the lower-risk stratum of LQT1 mutations, while still conferring substantial individual risk.

Kutyifa et al. (Ann Noninvasive Electrocardiol, 2018)66 Kutyifa et al. (Ann Noninvasive Electrocardiol, 2018)
1,923 Rochester LQTS Registry patients; 879 with LQT1; PMID 29504689 found that beta-blockers reduced cardiac event risk in LQT1 with a hazard ratio of 0.49 — roughly a 51% reduction in event rate. QTc greater than 500 ms and proband status were independent risk predictors in LQT1.

Priori et al. (NEJM, 2003)77 Priori et al. (NEJM, 2003)
647 LQTS patients, multivariate risk stratification; PMID 12736279 found that 30% of LQT1 carriers experienced a first cardiac event by age 40, with genetic locus and QTc interval as independent predictors. Cumulative cardiac event probability by age 50 is approximately 44% in untreated LQT1 carriers, falling to around 56% remaining event-free with appropriate treatment at age 50.

Practical Actions

This is an autosomal dominant condition: each first-degree relative has a 50% probability of carrying this variant. Cascade genetic testing of all first-degree relatives (parents, siblings, children) is the single most important clinical action after a proband is identified. Relatives who test negative need no further LQT1-specific surveillance.

Beta-blocker therapy — nadolol preferred88 nadolol preferred
Long-acting agents improve adherence and maintain 24-hour sympathetic blockade; short-acting metoprolol has shown higher recurrence rates in LQTS; GeneReviews NBK1129 2024 over metoprolol — is the pharmacological cornerstone of LQT1 management. ICD implantation is reserved for patients who have survived cardiac arrest, experience beta-blocker-resistant syncope, or cannot tolerate beta-blockers. Avoidance of QT-prolonging drugs is mandatory; check CredibleMeds.org before starting any new medication.

Swimming requires individual risk assessment: competitive swimming and unaccompanied swimming in any setting carry particular risk in LQT1. Most cardiac events during swimming occur without warning. Supervised recreational swimming on beta-blockers is generally considered lower-risk, but the decision should be made with a cardiologist familiar with LQT1.

Interactions

KCNQ1 variants interact with KCNE1 variants (rs1805123, MinK S38G) that encode the IKs beta subunit. Carriers of loss-of-function KCNQ1 variants who also carry KCNE1 loss-of-function variants may have compound IKs channel impairment producing more severe QT prolongation than either variant alone. Homozygosity for KCNQ1 pathogenic variants — or compound heterozygosity with a second KCNQ1 loss-of-function allele — causes Jervell and Lange-Nielsen syndrome (JLNS), characterized by profound QT prolongation, congenital sensorineural deafness, and a very high rate of life-threatening arrhythmias. JLNS follows autosomal recessive inheritance; heterozygous parents of JLNS probands each carry one KCNQ1 pathogenic allele and warrant LQT1 evaluation.

Drug Interactions

sotalol contraindicated literature
amiodarone dose_adjustment literature
azithromycin contraindicated literature
fluoroquinolones contraindicated literature
haloperidol contraindicated literature
methadone contraindicated literature
ondansetron increased_toxicity literature
hydroxychloroquine increased_toxicity literature

Genotype Interpretations

What each possible genotype means for this variant.

II Non-carrier Normal

No KCNQ1 c.1124_1127del variant — normal IKs channel function at this locus

You carry two intact copies of KCNQ1 at this position and do not have the c.1124_1127del frameshift deletion associated with Long QT syndrome type 1. Your IKs potassium channel function is not impaired by this specific variant. This variant is extremely rare — detected in fewer than 4 per million alleles in population databases — so the vast majority of people share this normal genotype.

DI LQT1 Carrier High Risk

One copy of pathogenic KCNQ1 frameshift — Long QT syndrome type 1

The c.1124_1127del deletion shifts the KCNQ1 reading frame at codon 375, producing a truncated protein that is degraded rather than incorporated into functional IKs channels. The surviving wild-type allele produces only about half the normal amount of IKs current — a haploinsufficiency mechanism. During exercise and emotional stress, sympathetic activation normally increases IKs current to accelerate cardiac repolarization as heart rate rises. With haploinsufficiency, the QT interval fails to shorten adequately, creating a period of electrical vulnerability during which a premature ventricular depolarization can trigger torsades de pointes (polymorphic ventricular tachycardia) and potentially ventricular fibrillation.

Swimming carries particular risk in LQT1 because it combines intense sympathetic activation with sudden face-immersion vagal reflexes — a dual trigger not present in other forms of exercise. Cardiac events during swimming frequently occur without premonitory warning and in supervised settings; lifeguards have reported drowning events in individuals later found to carry KCNQ1 pathogenic variants.

Prognostic factors that increase individual risk within LQT1: QTc greater than 500 ms, proband status (identified through clinical event rather than cascade testing), male sex before adolescence, and female sex after adolescence. Frameshift mutations like c.1124_1127del produce haploinsufficiency and are on average less severe than transmembrane dominant-negative mutations (HR 2.26 lower risk), but individual risk stratification requires cardiology evaluation.

ClinVar (VCV000052962.30) documents this variant in multiple unrelated families with cardiac events. It is not observed at meaningful frequency in gnomAD population databases (~4 per million alleles, consistent with strong negative selection).

DD Homozygous / Jervell-Lange-Nielsen Risk High Risk

Two copies of pathogenic KCNQ1 frameshift — severe LQT syndrome or Jervell-Lange-Nielsen syndrome

The IKs channel normally operates as an alpha-subunit tetramer (four KCNQ1 subunits) assembled with KCNE1 beta subunits. Homozygous loss-of-function means no functional IKs channels are produced at all. Without IKs, cardiac repolarization depends entirely on the IKr current (KCNH2/hERG) and other smaller currents — a fragile system that cannot adequately accelerate repolarization during tachycardia or sympathetic activation.

Classic Jervell and Lange-Nielsen syndrome features: QTc typically >500–550 ms (often

600 ms), bilateral sensorineural hearing loss present from birth (IKs is also critical for endolymph homeostasis in the cochlea), and cardiac events beginning in early childhood (mean age of first event ~3 years in some series). Sudden death rates without treatment are very high.

Even if this genotype does not produce full JLNS (which requires biallelic loss-of-function), the phenotype is expected to be substantially more severe than heterozygous LQT1. Specialist evaluation and high-dose beta-blockers or ICD are likely to be recommended.