KCTD7

Chr 7AR

potassium channel tetramerization domain containing 7

ENSG00000243335 UniProt: Q96MP8 OMIM: 611725

This gene encodes a member of the potassium channel tetramerization domain-containing protein family that may control excitability of cortical neurons. Mutations cause progressive myoclonic epilepsy-3 with or without intracellular inclusions, inherited in an autosomal recessive pattern. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.654), consistent with its role in neuronal excitability control.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that mediates the ubiquitination of multiple substrates, leading to either their proteasomal or lysosomal degradation, or modulating their activity through non-degradative ubiquitination (PubMed:36964131, PubMed:35921411). Regulates voltage-gated potassium channels, thereby modulating hyperpolarizing potassium currents in neurons and inducing potassium-dependent membrane hyperpolarization. Also regulates the neuronal glutamine transporter SLC38A2/SAT2, influencing neurotransmitter precursor availability (PubMed:27742667). Regulates calpain activity via atypical, non-degradative ubiquitination by mediating ubiquitination of CAPN1 via 'Lys6'-, 'Lys27'-, 'Lys29'-, and 'Lys63'-linked chains, and CAPN2 via 'Lys6'-linked chains, thereby preventing calpain autolysis (PubMed:36964131). Promotes lysosomal enzyme trafficking and maintains lysosomal function by acting as an endogenous regulator of CLN5, enhancing its ubiquitination and proteasomal degradation (PubMed:35921411)

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.651 OMIM phenotype

Clinical Summary— KCTD7

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Gene-Disease Validity (ClinGen)

progressive myoclonus epilepsy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.65LOEUF

pLI 0.001

Z-score 2.90

OE 0.39 (0.24–0.65)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.47Z-score

OE missense 0.75 (0.67–0.84)

210 obs / 279.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.39 (0.24–0.65)

0≤0.351.4

Missense OE?0.75 (0.67–0.84)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 10 / 25.9Missense obs/exp: 210 / 279.0Syn Z: 0.75

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKCTD7-related progressive myoclonic epilepsyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6936th %ile

GOF

0.5856th %ile

LOF

0.2776th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.