KCTD3

Chr 1

potassium channel tetramerization domain containing 3

Also known as: NY-REN-45

NCBI Gene: 51133 ENSG00000136636 UniProt: Q9Y597

KCTD3 encodes an accessory subunit that regulates hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) by increasing its cell surface expression and current density. Mutations cause neuronal migration disorders and developmental delays with autosomal recessive inheritance. The gene is highly constrained against loss-of-function variants, indicating that complete loss of KCTD3 function is likely pathogenic.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the potassium channel tetramerization-domain containing (KCTD) protein family. Members of this protein family regulate the biophysical characteristics of ion channels. In mouse, this protein interacts with hyperpolarization-activated cyclic nucleotide-gated channel complex 3 and enhances its cell surface expression and current density. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ResearchGenerating clinical summary…

LOEUF 0.41

Clinical Summary— KCTD3

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 80 VUS of 115 total submissions

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.101

Z-score 4.63

OE 0.25 (0.16–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.76Z-score

OE missense 0.62 (0.56–0.69)

263 obs / 422.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.25 (0.16–0.41)

0≤0.351.4

Missense OE?0.62 (0.56–0.69)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 11 / 44.2Missense obs/exp: 263 / 422.5Syn Z: 1.37

ClinVar Variant Classifications

115 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS80

Likely Benign7

Benign2

Conflicting1

Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	1	0	2
Likely Pathogenic	0	0	0	0	0
VUS	5	72	3	0	80
Likely Benign	0	3	2	2	7
Benign	0	1	0	1	2
Conflicting	—				1
Total	6	76	6	3	92

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap KCTD3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →