KCNQ1

Chr 11ADAR

potassium voltage-gated channel subfamily Q member 1

Also known as: ATFB1, ATFB3, JLNS1, KCNA8, KCNA9, KVLQT1, Kv1.9, Kv7.1

NCBI Gene: 3784 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a voltage-gated potassium channel required for repolarization phase of the cardiac action potential. This protein can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. Mutations in this gene are associated with hereditary long QT syndrome 1 (also known as Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation. This gene exhibits tissue-specific imprinting, with preferential expression from the maternal allele in some tissues, and biallelic expression in others. This gene is located in a region of chromosome 11 amongst other imprinted genes that are associated with Beckwith-Wiedemann syndrome (BWS), and itself has been shown to be disrupted by chromosomal rearrangements in patients with BWS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

133 unique Pathogenic / Likely Pathogenic· 229 VUS of 788 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — KCNQ1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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 OE?0.54 (0.37–0.81)

0≤0.351.4

Missense OE?0.74 (0.67–0.82)

0≤0.61.4

Synonymous OE?1.17

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

This gene — mechanism propensity

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 · 57% of P/LP variants are LoF · ClinGen HI: Sufficient evidence for dosage pathogenicity

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.1

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).2

LOFAsymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction3

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

788 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic59

Likely Pathogenic74

VUS229

Likely Benign281

Benign67

Conflicting73

Pathogenic

Likely Pathogenic

229

VUS

281

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	36	12	11	0	59
Likely Pathogenic	40	32	2	0	74
VUS	2	187	36	4	229
Likely Benign	0	5	135	141	281
Benign	0	1	64	2	67
Conflicting	—				73
Total	78	237	248	147	783

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

6 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap KCNQ1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →