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

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. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shal-related subfamily, members of which form voltage-activated A-type potassium ion channels and are prominent in the repolarization phase of the action potential. This member includes two isoforms with different sizes, which are encoded by alternatively spliced transcript variants of this gene. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

28 unique Pathogenic / Likely Pathogenic· 299 VUS of 724 total submissions

Explore recent and relevant literature in Research Assistant →

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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 OE?0.09 (0.04–0.28)

0≤0.351.4

Missense OE?0.48 (0.43–0.54)

0≤0.61.4

Synonymous OE?0.95

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

This gene — mechanism propensity

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 · 100% of P/LP are missense

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.1

GOFTransient outward current (I-to) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome2

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

724 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10

Likely Pathogenic18

VUS299

Likely Benign333

Benign25

Conflicting34

Pathogenic

Likely Pathogenic

299

VUS

333

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	10	0	0	10
Likely Pathogenic	0	18	0	0	18
VUS	6	280	9	4	299
Likely Benign	0	10	61	262	333
Benign	0	0	20	5	25
Conflicting	—				34
Total	6	318	90	271	719

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap KCND3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →