KCNH8

Chr 3

potassium voltage-gated channel subfamily H member 8

Also known as: ELK, ELK1, Kv12.1, elk3, hElk-1

NCBI Gene: 131096 ENSG00000183960 UniProt: Q96L42 OMIM: 608260

KCNH8 encodes a pore-forming subunit of a voltage-gated potassium channel that mediates slowly activating, non-inactivating outward potassium currents in response to membrane depolarization. Mutations cause epileptic encephalopathy with developmental delay and intellectual disability, following an autosomal dominant inheritance pattern. The condition typically presents in early childhood with seizures and neurodevelopmental impairment.

OMIM ResearchSummary from RefSeq, UniProt

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. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.67

Clinical Summary— KCNH8

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 122 VUS of 143 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.67LOEUF

pLI 0.000

Z-score 3.51

OE 0.48 (0.35–0.67)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.20Z-score

OE missense 0.86 (0.80–0.93)

509 obs / 591.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.48 (0.35–0.67)

0≤0.351.4

Missense OE?0.86 (0.80–0.93)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 25 / 52.4Missense obs/exp: 509 / 591.2Syn Z: -1.14

This gene — mechanism propensity

0.79top 25%

GOF

0.82top 10%

LOF

0.3067th %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

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.

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

ClinVar Variant Classifications

143 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS122

Likely Benign4

Benign3

Likely Pathogenic

122

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	1	0	1
VUS	122	0	122
Likely Benign	2	2	4
Benign	2	1	3
Total	127	3	130

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

View in ClinVar →

25 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap KCNH8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →