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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene is a member of the KCNQ potassium channel gene family that is differentially expressed in subregions of the brain and in skeletal muscle. The protein encoded by this gene yields currents that activate slowly with depolarization and can form heteromeric channels with the protein encoded by the KCNQ3 gene. Currents expressed from this protein have voltage dependences and inhibitor sensitivities in common with M-currents. They are also inhibited by M1 muscarinic receptor activation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

34 unique Pathogenic / Likely Pathogenic· 382 VUS of 899 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — KCNQ5

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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 OE?0.17 (0.10–0.31)

0≤0.351.4

Missense OE?0.58 (0.53–0.64)

0≤0.61.4

Synonymous OE?1.17

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

This gene — mechanism propensity

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 · 41% of P/LP variants are LoF · 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.1

GOFLoss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy2

LOFThis evidence strongly supports the hypothesis of KCNQ5 haploinsufficiency, which could lead to altered neuronal excitability, thus contributing to seizure susceptibility and intellectual disability.3

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

899 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20

Likely Pathogenic14

VUS382

Likely Benign348

Benign86

Conflicting40

Pathogenic

Likely Pathogenic

382

VUS

348

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	10	9	1	0	20
Likely Pathogenic	4	10	0	0	14
VUS	18	344	16	4	382
Likely Benign	3	35	92	218	348
Benign	0	58	11	17	86
Conflicting	—				40
Total	35	456	120	239	890

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap KCNQ5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →