KCNQ5

Chr 6AD

potassium voltage-gated channel subfamily Q member 5

Also known as: Kv7.5, MRD46

NCBI Gene: 56479 ENSG00000185760 UniProt: Q9NR82 OMIM: 607357

The protein encodes a potassium channel that generates M-currents and forms heteromeric channels with KCNQ3, with expression in brain subregions and skeletal muscle. Loss-of-function mutations cause autosomal dominant intellectual developmental disorder. The high constraint scores (pLI 0.98, LOEUF 0.31) indicate the gene is highly intolerant to loss-of-function variants, consistent with the dominant inheritance pattern where haploinsufficiency leads to disease.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

MultiplemechanismADLOEUF 0.311 OMIM phenotype

Clinical Summary— KCNQ5

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.31LOEUF

pLI 0.980

Z-score 5.29

OE 0.17 (0.10–0.31)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

3.32Z-score

OE missense 0.58 (0.53–0.64)

289 obs / 497.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.17 (0.10–0.31)

0≤0.351.4

Missense OE0.58 (0.53–0.64)

0≤0.61.4

Synonymous OE1.17

0≤1.21.6

LoF obs/exp: 8 / 47.2Missense obs/exp: 289 / 497.2Syn Z: -1.80

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedKCNQ5-related intellectual disability with or without epileptic encephalopathy, activatingGOFAD

strongKCNQ5-related intellectual disability with or without epileptic encephalopathyLOFAD

0.6939th %ile

GOF

0.76top 25%

LOF

0.65top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.31

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

DNWhen mutant channels were co-expressed with wild-type (WT) KV7.5 or KV7.5 and KV7.3 channels, three variants also revealed a significant dominant-negative effect on WT channels.PMID:36088682

GOFLoss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic EncephalopathyPMID:28669405

LOFThis evidence strongly supports the hypothesis of KCNQ5 haploinsufficiency, which could lead to altered neuronal excitability, thus contributing to seizure susceptibility and intellectual disability.PMID:30359776

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