KCND3

Chr 1AD

potassium voltage-gated channel subfamily D member 3

Also known as: BRGDA9, KCND3L, KCND3S, KSHIVB, KV4.3, SCA19, SCA22

NCBI Gene: 3752 ENSG00000171385 UniProt: Q9UK17 OMIM: 605411

The KCND3 protein forms the pore-forming subunit of voltage-gated A-type potassium channels that mediate fast-activating, rapidly-inactivating potassium currents in neurons and cardiomyocytes, playing a critical role in action potential repolarization. Autosomal dominant mutations cause spinocerebellar ataxia 19 and Brugada syndrome 9, likely through dominant-negative effects given the gene's extreme intolerance to loss-of-function variants. The pathogenic mechanism involves disrupted potassium channel function affecting neuronal excitability in the cerebellum and cardiac repolarization.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.282 OMIM phenotypes

Clinical Summary— KCND3

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Gene-Disease Validity (ClinGen)

Brugada syndrome 1 · ADDisputed

Disputed — evidence questions this relationship

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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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GeneReview available — KCND3

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

0.28LOEUF

pLI 0.990

Z-score 4.01

OE 0.09 (0.04–0.28)

Highly constrained

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

Missense Constraint

3.85Z-score

OE missense 0.48 (0.43–0.54)

209 obs / 435.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.09 (0.04–0.28)

0≤0.351.4

Missense OE0.48 (0.43–0.54)

0≤0.61.4

Synonymous OE0.95

0≤1.21.6

LoF obs/exp: 2 / 22.6Missense obs/exp: 209 / 435.3Syn Z: 0.55

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongKCND3-related neurodevelopmental disorder with cerebellar ataxia and movement disordersOTHERAD

limitedKCND3-related Brugada syndromeOTHERAD

0.6261th %ile

GOF

0.74top 25%

LOF

0.57top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative 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 · 1 literature citation

DNprediction above median · 1 literature citation

LOFLOEUF 0.28

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

DNThis implies that the SCA19 mutants described here must have a dominant negative action on the maturation and/or function of the other complex members and cause a loss of Kv4.3 function.PMID:23280838

GOFTransient outward current (I-to) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndromePMID:22457051

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.