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

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.