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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit of a voltage-gated non-inactivating delayed rectifier potassium channel. It is activated at the onset of myoblast differentiation. The gene is highly expressed in brain and in myoblasts. Overexpression of the gene may confer a growth advantage to cancer cells and favor tumor cell proliferation. Alternative splicing of this gene results in two transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

28 unique Pathogenic / Likely Pathogenic· 388 VUS of 904 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — KCNH1

Authoritative clinical overview · Recommended first read

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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 OE?0.21 (0.13–0.39)

0≤0.351.4

Missense OE?0.55 (0.50–0.61)

0≤0.61.4

Synonymous OE?0.99

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.1

This gene — mechanism propensity

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 · 100% of P/LP are missense

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 e2

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

904 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15

Likely Pathogenic13

VUS388

Likely Benign373

Benign68

Conflicting36

Pathogenic

Likely Pathogenic

388

VUS

373

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	15	0	0	15
Likely Pathogenic	0	13	0	0	13
VUS	23	344	19	2	388
Likely Benign	4	50	103	216	373
Benign	0	18	40	10	68
Conflicting	—				36
Total	27	440	162	228	893

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

View in ClinVar →

18 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap KCNH1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →