KCNQ3

Chr 8AD

potassium voltage-gated channel subfamily Q member 3

Also known as: BFNC2, EBN2, KV7.3

NCBI Gene: 3786 ENSG00000184156 UniProt: O43525 OMIM: 602232

The protein forms M-channels by associating with KCNQ2 or KCNQ5 to regulate neuronal excitability, with these channels being inhibited by muscarinic acetylcholine receptors and activated by retigabine. Mutations cause benign familial neonatal convulsions type 2 through an autosomal dominant inheritance pattern. The pathogenic mechanism involves gain-of-function mutations that alter normal channel function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein that functions in the regulation of neuronal excitability. The encoded protein forms an M-channel by associating with the products of the related KCNQ2 or KCNQ5 genes, which both encode integral membrane proteins. M-channel currents are inhibited by M1 muscarinic acetylcholine receptors and are activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 2 (BFNC2), also known as epilepsy, benign neonatal type 2 (EBN2). Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.361 OMIM phenotype

VCEP Guidelines: KCNQ Brain DisordersIn Progress

ClinGen Panel

Clinical Summary— KCNQ3

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.80) — some intolerance to loss-of-function variants.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.36LOEUF

pLI 0.801

Z-score 4.74

OE 0.20 (0.12–0.36)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.07Z-score

OE missense 0.73 (0.67–0.80)

350 obs / 477.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.20 (0.12–0.36)

0≤0.351.4

Missense OE?0.73 (0.67–0.80)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 8 / 40.5Missense obs/exp: 350 / 477.1Syn Z: 0.41

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKCNQ3-related syndromeOTHERAD

This gene — mechanism propensity

0.7131th %ile

GOF

0.79top 25%

LOF

0.54top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). 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

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

DNPatch-clamp analysis revealed no current with the mutant homomer and reduced current with heterotetramer (KCNQ2WT/KCNQ2G281R/KCNQ3WT) channels, consistent with a dominant-negative effect.1

GOFAutism and developmental disability caused by KCNQ3 gain-of-function variants.2

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

References