KCNV1

Chr 8

potassium voltage-gated channel modifier subfamily V member 1

Also known as: HNKA, KCNB3, KV2.3, KV8.1

NCBI Gene: 27012 ENSG00000164794 UniProt: Q6PIU1 OMIM: 608164

This protein is a voltage-gated potassium channel subunit that modulates the activity of other potassium channels (KCNB1, KCNB2, KCNC4, and KCND1) by altering their inactivation properties and potentially reducing their function by retaining them in intracellular membranes. Mutations cause autosomal dominant epilepsy, typically with infantile or early childhood onset. KCNV1 is highly constrained against loss-of-function variants (pLI = 0.98, LOEUF = 0.30), indicating that functional copies are essential for normal neurological development.

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 voltage-gated channel subfamily V. This protein is essentially present in the brain, and its role might be to inhibit the function of a particular class of outward rectifier potassium channel types. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.29

Clinical Summary— KCNV1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). 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?

0.29LOEUF

pLI 0.978

Z-score 3.49

OE 0.06 (0.02–0.29)

Highly constrained

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

Missense Constraint?

4.07Z-score

OE missense 0.33 (0.28–0.39)

95 obs / 289.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.29)

0≤0.351.4

Missense OE?0.33 (0.28–0.39)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 1 / 16.1Missense obs/exp: 95 / 289.9Syn Z: -0.66

This gene — mechanism propensity

0.5869th %ile

GOF

0.78top 25%

LOF

0.4233th %ile

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

LOFLOEUF 0.29

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.