KCNQ1

Chr 11ADAR

potassium voltage-gated channel subfamily Q member 1

ENSG00000053918 UniProt: P51787 OMIM: 607542

This gene encodes a voltage-gated potassium channel subunit that is essential for cardiac repolarization and also functions in the inner ear, stomach, and colon. Mutations cause long QT syndrome type 1 (Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, short QT syndrome type 2, and familial atrial fibrillation, with inheritance patterns that are autosomal dominant for isolated cardiac phenotypes and autosomal recessive for Jervell and Lange-Nielsen syndrome which includes both cardiac arrhythmias and congenital deafness. The gene is extremely intolerant to loss-of-function variants (pLI near 0, LOEUF 0.81), reflecting its critical role in cardiac and auditory function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAD/ARLOEUF 0.815 OMIM phenotypes

Clinical Summary— KCNQ1

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Gene-Disease Validity (ClinGen)

Jervell and Lange-Nielsen syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

4 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

0.81LOEUF

pLI 0.000

Z-score 2.37

OE 0.54 (0.37–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint

1.83Z-score

OE missense 0.74 (0.67–0.82)

295 obs / 397.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.54 (0.37–0.81)

0≤0.351.4

Missense OE0.74 (0.67–0.82)

0≤0.61.4

Synonymous OE1.17

0≤1.21.6

LoF obs/exp: 17 / 31.3Missense obs/exp: 295 / 397.8Syn Z: -1.73

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKCNQ1-related long QT syndromeLOFAR

definitiveKCNQ1-related long QT syndromeLOFAD

limitedKCNQ1-related hypertrophic cardiomyopathyOTHERAD

strongKCNQ1-related short QT syndromeGOFAD

definitiveKCNQ1-related Jervell and Lange-Nielsen syndromeLOFAR

0.87top 5%

GOF

0.88top 5%

LOF

0.3066th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median · 1 literature citation

LOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNThe Y111C/KCNQ1 mutation causes a dominant-negative effect in vitro but a benign clinical phenotype in a Swedish long QT syndrome population.PMID:21129503

GOFGain of function mutations in three genes encoding K(+) channels have been identified, explaining the abbreviated repolarization seen in this condition: KCNH2 for I(kr) (SQT1), KCNQ1 for I(ks) (SQT2) and KCNJ2 for I(k1) (SQT3).PMID:20126594

LOFAsymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunctionPMID:26669661

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.