KCNH3

Chr 12

potassium voltage-gated channel subfamily H member 3

Also known as: BEC1, ELK2, Kv12.2

NCBI Gene: 23416 ENSG00000135519 UniProt: Q9ULD8 OMIM: 604527

The protein is a voltage-gated inwardly rectifying potassium channel alpha subunit that exhibits rapid activation and inactivation, predominantly expressed in the forebrain. Mutations cause autosomal dominant developmental and epileptic encephalopathy and neurodevelopmental disorder with seizures and brain atrophy, affecting cognitive development and seizure control. This gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to have significant clinical consequences.

OMIM ResearchSummary from RefSeq, UniProt

MultiplemechanismLOEUF 0.25

Clinical Summary— KCNH3

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). 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

0.25LOEUF

pLI 0.999

Z-score 5.34

OE 0.12 (0.06–0.25)

Highly constrained

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

Missense Constraint

3.85Z-score

OE missense 0.59 (0.54–0.64)

403 obs / 686.6 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.12 (0.06–0.25)

0≤0.351.4

Missense OE0.59 (0.54–0.64)

0≤0.61.4

Synonymous OE0.95

0≤1.21.6

LoF obs/exp: 5 / 42.6Missense obs/exp: 403 / 686.6Syn Z: 0.69

0.5477th %ile

GOF

0.77top 25%

LOF

0.60top 25%

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

LOFLOEUF 0.25

GOFprediction above median

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.

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