KCNC1

Chr 11AD

potassium voltage-gated channel subfamily C member 1

Also known as: EPM7, KV3.1, KV4, NGK2

NCBI Gene: 3746 ENSG00000129159 UniProt: P48547 OMIM: 176258

This gene encodes a voltage-gated potassium channel that controls potassium ion permeability across excitable cell membranes. Mutations cause progressive myoclonic epilepsy type 7, inherited in an autosomal dominant pattern. The high pLI score (0.99) and low LOEUF score (0.26) indicate the gene is highly intolerant to loss-of-function variants, suggesting haploinsufficiency as the likely pathogenic mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of a family of integral membrane proteins that mediate the voltage-dependent potassium ion permeability of excitable membranes. Alternative splicing is thought to result in two transcript variants encoding isoforms that differ at their C-termini. These isoforms have had conflicting names in the literature: the longer isoform has been called both "b" and "alpha", while the shorter isoform has been called both "a" and "beta" (PMIDs 1432046, 12091563). [provided by RefSeq, Oct 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.261 OMIM phenotype

Clinical Summary— KCNC1

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Gene-Disease Validity (ClinGen)

progressive myoclonus epilepsy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

16 unique Pathogenic / Likely Pathogenic· 267 VUS of 538 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — KCNC1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.26LOEUF

pLI 0.990

Z-score 3.73

OE 0.06 (0.02–0.26)

Highly constrained

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

Missense Constraint?

4.52Z-score

OE missense 0.36 (0.31–0.41)

139 obs / 390.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.26)

0≤0.351.4

Missense OE?0.36 (0.31–0.41)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 1 / 18.1Missense obs/exp: 139 / 390.2Syn Z: 1.28

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKCNC1-related epilepsy, progressive myoclonicGOFAD

This gene — mechanism propensity

0.5869th %ile

GOF

0.75top 25%

LOF

0.59top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, loss-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 · 81% of P/LP are missense

LOF19% of P/LP variants are LoF · LOEUF 0.26

DN1 literature citation

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

DNFunctional analysis of the Arg320His mutant channel showed a dominant-negative loss-of-function effect.1

GOFA novel KCNC1 gain-of-function variant causing developmental and epileptic encephalopathy: Precision medicine approach with fluoxetine.2

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

538 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic15

VUS267

Likely Benign226

Benign14

Conflicting14

Pathogenic

Likely Pathogenic

267

VUS

226

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	3	12	0	0	15
VUS	10	248	6	3	267
Likely Benign	0	8	22	196	226
Benign	0	0	7	7	14
Conflicting	—				14
Total	13	269	35	206	537

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap KCNC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →