KCNH1

Chr 1AD

potassium voltage-gated channel subfamily H member 1

Also known as: EAG, EAG1, K(V)10.1, Kv10.1, TMBTS, ZLS1, h-eag, hEAG

NCBI Gene: 3756 ENSG00000143473 UniProt: O95259 OMIM: 603305

The protein forms voltage-gated potassium channels that regulate neuronal excitability and is highly expressed in brain and muscle. Gain-of-function mutations cause Temple-Baraitser syndrome and Zimmermann-Laband syndrome 1, both inherited in an autosomal dominant pattern. The pathogenic mechanism involves altered potassium channel function that disrupts normal neuronal signaling.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

GOFmechanismADLOEUF 0.392 OMIM phenotypes

Clinical Summary— KCNH1

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Gene-Disease Validity (ClinGen)

KCNH1 associated disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.55) — some intolerance to loss-of-function variants.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint

0.39LOEUF

pLI 0.546

Z-score 4.45

OE 0.21 (0.13–0.39)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

3.82Z-score

OE missense 0.55 (0.50–0.61)

317 obs / 574.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.21 (0.13–0.39)

0≤0.351.4

Missense OE0.55 (0.50–0.61)

0≤0.61.4

Synonymous OE0.99

0≤1.21.6

LoF obs/exp: 8 / 37.3Missense obs/exp: 317 / 574.3Syn Z: 0.14

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongKCNH1-related Temple-Baraitser syndromeGOFAD

strongKCNH1-related Zimmermann-Laband syndromeOTHERAD

Mechanism Note (expert annotation)

GOF

EAG1 (Kv10.1) — functional studies demonstrate constitutive channel activation (GOF) with shifted voltage dependence, not dominant-negative effects.

References:PMID:25741867

0.7229th %ile

GOF

0.81top 10%

LOF

0.4332th %ile

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

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

GOFZLS is caused by heterozygous gain-of-function variants in KCNH1 or KCNN3, and gain-of-function KCNK4 variants underlie the clinically similar FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth) syndrome; KCNH1, KCNN3 and KCNK4 ePMID:32622958

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