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

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]

Primary Disease Associations & Inheritance

Temple-Baraitser syndromeMIM #611816

Zimmermann-Laband syndrome 1MIM #135500

587

ClinVar variants

Pathogenic / LP

0.55

pLI score

Active trials

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

16 Pathogenic / Likely Pathogenic· 255 VUS of 587 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.21 (0.13–0.39)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.55 (0.50–0.61)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99

0≤1.21.6

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