rs397508072 — KCNQ1 Q356X

Nonsense mutation in the cardiac IKs potassium channel causing premature protein truncation; heterozygous carriers develop Romano-Ward long QT syndrome type 1 with risk of life-threatening arrhythmia, while homozygous carriers develop Jervell and Lange-Nielsen syndrome with congenital deafness

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KCNQ1 Q356X — When the Heart's Repolarization Brake Is Cut

Every heartbeat ends with a carefully timed electrical recovery — the repolarization phase11 repolarization phase
Phase 3 of the ventricular action potential, lasting roughly 250-350 ms, during which potassium ions flow out of cardiomyocytes to restore the negative resting membrane potential. The speed of repolarization determines the QT interval on the ECG that resets the cardiac muscle for the next beat. The KCNQ1 gene encodes the pore-forming subunit of the IKs potassium channel — a key contributor to that electrical reset. The Q356X variant (NM_000218.3:c.1066C>T) introduces a premature stop codon at position 356, cutting the 676-amino-acid protein roughly in half. The truncated mRNA is degraded by nonsense-mediated decay22 nonsense-mediated decay
A cellular quality-control mechanism that degrades mRNA transcripts containing premature stop codons, preventing production of potentially toxic truncated proteins, producing a loss-of-function through haploinsufficiency rather than a dominant-negative mechanism. The result: insufficient IKs current, impaired ventricular repolarization, a prolonged QT interval on the ECG, and a substrate for life-threatening arrhythmia.

The variant is classified Pathogenic in ClinVar VCV00004595033 ClinVar VCV000045950
ClinVar Variation ID 45950; multiple submitters, no conflicts, 2-star review status and is associated with both Romano-Ward LQT syndrome type 1 (autosomal dominant, heterozygous) and the more severe Jervell and Lange-Nielsen syndrome type 1 (autosomal recessive, homozygous or compound heterozygous, with congenital deafness).

The Mechanism

The IKs channel is a hetero-octamer: four KCNQ1 α-subunits form the central potassium-conducting pore, flanked by regulatory KCNE1 (MinK) β-subunits. Together they generate the slow delayed rectifier current that activates during sustained depolarization and provides the repolarization reserve that becomes especially critical during exercise, when heart rate and sympathetic tone increase. The Q356X truncation falls in the intracellular C-terminus of KCNQ1, beyond the S6 transmembrane helix. Because the truncated protein undergoes nonsense-mediated mRNA decay, heterozygous carriers produce approximately 50% of normal IKs current — a haploinsufficient mechanism44 haploinsufficient mechanism
Haploinsufficiency occurs when one functional copy of a gene is insufficient to maintain normal function; in contrast, dominant-negative mutations produce a defective protein that actively poisons the remaining normal copies, typically causing more severe channel dysfunction. IKs haploinsufficiency prolongs the cardiac action potential and QT interval, particularly under adrenergic stress. When IKs reserve is absent, a triggered premature beat can induce [Torsades de pointes | A polymorphic ventricular tachycardia that on the ECG appears to twist around the isoelectric line; it often self-terminates but can degenerate into ventricular fibrillation and cardiac arrest] — a rapid, disorganized ventricular arrhythmia that can lead to syncope, cardiac arrest, or sudden death.

Homozygous or compound heterozygous Q356X carriers lack functional IKs entirely. KCNQ1 is also expressed in the stria vascularis of the cochlea, where IKs maintains the endocochlear potential required for hair-cell mechanotransduction. Complete IKs ablation causes profound bilateral sensorineural deafness alongside the severe cardiac phenotype of Jervell and Lange-Nielsen syndrome.

The Evidence

The Q356X variant's pathogenicity derives from multiple lines of evidence. At the population level, the T allele is essentially absent from gnomAD (approximately 10 observed alleles across 1.4 million), consistent with strong negative selection.

Mutation spectrum data: Splawski et al. 200055 Splawski et al. 2000
Spectrum of mutations in LQT genes, 262 unrelated patients; KCNQ1 accounted for 42% of identified mutations; stop-gain and frameshift mutations as a class represent 5-7% of KCNQ1 LQT1 variants established that nonsense mutations in KCNQ1 consistently segregate with disease in affected families.

Mutation-type risk stratification: The landmark Moss et al. 2007 Circulation66 Moss et al. 2007 Circulation
600 LQT1 patients across 101 families from three international registries; independent predictors of cardiac events assessed through age 40 study established that truncating mutations (which cause haploinsufficiency) carry a meaningfully lower clinical event risk than dominant-negative missense mutations (HR 2.26 for dominant-negative vs haploinsufficiency), though both are clinically significant.

Stop-codon-specific data: Ruwald et al. 2015 Heart Rhythm77 Ruwald et al. 2015 Heart Rhythm
1,090 LQT1 patients from the International Long QT Registry; stop-codon mutations specifically vs other mutation types found that KCNQ1 stop-codon carriers had a 27% cumulative cardiac event rate by age 40 versus 44% for non-C-loop missense carriers (HR 0.57, p=0.035). This reduced — but still substantial — risk reflects the haploinsufficiency mechanism. Importantly, only 1 aborted cardiac arrest occurred among stop-codon carriers during the follow-up period.

JLNS severity: Homozygous biallelic KCNQ1 loss-of-function produces a far more severe phenotype. Per GeneReviews, more than 50% of untreated JLNS patients die before age 15, and 50% have a cardiac event before age 3. Beta-blockers provide only partial protection in JLNS (51% of patients still experience events despite therapy).

Practical Actions

Romano-Ward (CT heterozygotes): The trigger profile of LQT1 is distinctive — 62% of life-threatening events occur during exercise or emotional arousal, with swimming particularly implicated. Beta-blockers (nadolol or propranolol preferred over selective agents) reduce cardiac events by approximately 50-80% in LQT1. Unsupervised swimming and competitive athletics should be restricted until formal cardiac evaluation and, if applicable, ICD placement are completed.

JLNS (TT homozygotes): Management requires urgent pediatric cardiology and audiology referral. Beta-blockers are first-line but have limited efficacy (51% event rate despite therapy). ICD is strongly recommended given the extreme arrhythmia burden and early onset. Left cardiac sympathetic denervation (LCSD) may reduce events in ICD-ineligible or refractory cases. Cochlear implantation addresses the deafness component.

Interactions

KCNQ1 Q356X belongs to the class of truncating KCNQ1 variants that cause loss of function through haploinsufficiency. KCNE1 (MinK), the regulatory β-subunit that assembles with KCNQ1 to form the IKs channel, is also a cause of LQT syndrome (LQT5, OMIM 613695) and JLNS type 2 when mutated. Patients who carry both a KCNQ1 variant and a KCNE1 variant (compound digenic heterozygosity) can exhibit more severe IKs impairment than either alone. Other LQT genes — KCNH2 (LQT2), SCN5A (LQT3) — affect independent ion channels; concurrent variants in these genes (digenic LQTS) are associated with more severe QT prolongation and higher sudden-death risk than single-gene LQTS.

Genotype Interpretations

What each possible genotype means for this variant.

CC No Q356X Variant Normal

No KCNQ1 Q356X mutation — standard arrhythmia risk from this variant

You carry two copies of the normal KCNQ1 allele at this position and do not have the Q356X truncating mutation. Your IKs potassium channel function is unaffected by this specific variant. Virtually the entire global population shares this result — the T allele appears at only about 1 in 140,000 alleles in population databases. Other KCNQ1 variants, as well as variants in KCNH2, SCN5A, and other ion-channel genes, can independently cause long QT syndrome and are not captured by this result.

CT LQT1 Carrier High Risk

Carries one copy of KCNQ1 Q356X — pathogenic for Romano-Ward long QT syndrome type 1

The Q356X variant (NM_000218.3:c.1066C>T) introduces a premature stop at codon 356 of the 676-amino-acid KCNQ1 protein. The C-terminal domain truncated by this stop codon contains the coiled-coil assembly domain essential for KCNQ1 tetramer formation and the calmodulin-binding helix B critical for adrenergic responsiveness. The truncated mRNA undergoes nonsense-mediated decay, so haploinsufficiency — not dominant-negative poisoning — is the mechanism. This mechanistic distinction has clinical implications: in a registry study of 1,090 LQT1 patients (Ruwald et al. 2015), stop-codon carriers had a significantly lower cardiac event rate (HR 0.57, p=0.035) compared to the most dangerous (C-loop missense) genotypes, with only one aborted cardiac arrest recorded during follow-up. Beta-blockers remain the cornerstone of treatment; 81% of LQT1 patients treated with beta-blockers are free of recurrences in some series.

The prototypical clinical trigger for LQT1 events is sympathetic activation — specifically swimming, competitive sports, sudden acoustic stimulation, or intense emotional arousal. This pattern reflects IKs's role as the repolarization reserve that normally accommodates faster heart rates. When IKs reserve is halved, the action potential cannot shorten adequately at high heart rates, and Torsades can be initiated by a triggered beat on the vulnerable T-wave peak.

Heterozygous carriers do not have congenital deafness — KCNQ1 haploinsufficiency is insufficient to impair cochlear IKs function, which requires biallelic loss.

TT Jervell and Lange-Nielsen Syndrome Homozygous

Carries two copies of KCNQ1 Q356X — associated with Jervell and Lange-Nielsen syndrome type 1

Complete absence of KCNQ1-mediated IKs has two major consequences. In the heart, total IKs loss produces markedly prolonged ventricular repolarization and a critically narrow repolarization reserve. Even modest increases in sympathetic tone — fever, exercise, emotional distress — can precipitate Torsades de pointes and ventricular fibrillation. In the inner ear, KCNQ1 and KCNE1 together maintain the endocochlear potential in the stria vascularis; biallelic loss abolishes this potential and destroys hair-cell function, causing congenital profound bilateral deafness. Gastric parietal cells also express KCNQ1, and JLNS patients frequently have elevated serum gastrin and iron-deficiency anemia as secondary features.

Management of JLNS requires a multidisciplinary team: pediatric electrophysiology, audiology, genetic counseling, and often anesthesiology coordination (many common anesthetic agents prolong the QT interval). The Norwegian and Swedish JLNS prevalence of 1 in 200,000 is driven by founder KCNQ1 variants; the Q356X variant is not known to be a founder allele in any population but shares the same biallelic pathogenic mechanism.