TBC1D24

Chr 16ADAR

TBC1 domain family member 24

Also known as: DEE16, DFNA65, DFNB86, DOORS, EIEE16, EIM, EPRPDC, FIME

NCBI Gene: 57465 ENSG00000162065 UniProt: Q9ULP9 OMIM: 613577

The protein functions as a GTPase-activating protein that regulates Rab small GTPases involved in membrane trafficking. Mutations cause a spectrum of disorders including developmental and epileptic encephalopathy, familial infantile myoclonic epilepsy, DOORS syndrome, and both autosomal dominant and recessive forms of deafness. The condition follows both autosomal dominant and autosomal recessive inheritance patterns, with pathogenicity resulting from disrupted membrane trafficking regulation.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein with a conserved domain, referred to as the TBC domain, characteristic of proteins which interact with GTPases. TBC domain proteins may serve as GTPase-activating proteins for a particular group of GTPases, the Rab (Ras-related proteins in brain) small GTPases which are involved in the regulation of membrane trafficking. Mutations in this gene are associated with familial infantile myoclonic epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 1.126 OMIM phenotypes

Clinical Summary— TBC1D24

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Gene-Disease Validity (ClinGen)

DOORS syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.12LOEUF

pLI 0.000

Z-score 1.14

OE 0.73 (0.49–1.12)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.76Z-score

OE missense 0.89 (0.81–0.97)

312 obs / 351.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.73 (0.49–1.12)

0≤0.351.4

Missense OE?0.89 (0.81–0.97)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 15 / 20.6Missense obs/exp: 312 / 351.9Syn Z: -0.99

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTBC1D24-related DOORS syndromeLOFAR

definitiveTBC1D24-related myoclonic epilepsy, infantile, familialOTHERAR

This gene — mechanism propensity

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

0.4785th %ile

GOF

0.5464th %ile

LOF

0.3941th %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.

Literature Evidence

LOFImportantly, heterozygous TBC1D24 mutation carriers have also been reported with seizures, suggesting that haploinsufficiency for TBC1D24 is significant clinically.1

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

References