TBCE

Chr 1AR

tubulin folding cofactor E

Also known as: HRD, KCS, KCS1, PEAMO, pac2

NCBI Gene: 6905 ENSG00000284770 UniProt: Q15813 OMIM: 604934

Cofactor E binds to the cofactor D/beta-tubulin complex and facilitates the release of correctly folded beta-tubulin committed to the native state, functioning as part of the tubulin folding pathway. Biallelic mutations cause autosomal recessive conditions including progressive encephalopathy with amyotrophy and optic atrophy, hypoparathyroidism-retardation-dysmorphism syndrome, and Kenny-Caffey syndrome type 1. The pathogenic mechanism appears to be dominant negative, disrupting proper microtubule formation essential for cellular structure and function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Cofactor E is one of four proteins (cofactors A, D, E, and C) involved in the pathway leading to correctly folded beta-tubulin from folding intermediates. Cofactors A and D are believed to play a role in capturing and stabilizing beta-tubulin intermediates in a quasi-native confirmation. Cofactor E binds to the cofactor D/beta-tubulin complex; interaction with cofactor C then causes the release of beta-tubulin polypeptides that are committed to the native state. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.813 OMIM phenotypes

Clinical Summary— TBCE

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Gene-Disease Validity (ClinGen)

encephalopathy, progressive, with amyotrophy and optic atrophy · ARModerate

Moderate evidence — consider for supplementary testing

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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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ClinVar Variants

84 unique Pathogenic / Likely Pathogenic· 193 VUS of 726 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TBCE

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.000

Z-score 2.44

OE 0.54 (0.37–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.12Z-score

OE missense 0.98 (0.89–1.08)

276 obs / 281.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.54 (0.37–0.81)

0≤0.351.4

Missense OE?0.98 (0.89–1.08)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 18 / 33.2Missense obs/exp: 276 / 281.7Syn Z: -0.40

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTBCE-related hypoparathyroidism-retardation-dysmorphism syndromeLOFAR

strongTBCE-related early-onset progressive encephalopathy with distal spinal muscular atrophyOTHERAR

This gene — mechanism propensity

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

0.6938th %ile

GOF

0.5955th %ile

LOF

0.2679th %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.

ClinVar Variant Classifications

726 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic58

Likely Pathogenic26

VUS193

Likely Benign323

Benign77

Conflicting31

Pathogenic

Likely Pathogenic

193

VUS

323

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	42	0	16	0	58
Likely Pathogenic	18	5	3	0	26
VUS	10	150	26	7	193
Likely Benign	1	14	158	150	323
Benign	1	2	70	4	77
Conflicting	—				31
Total	72	171	273	161	708

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

View in ClinVar →

51 pathogenic / likely-pathogenic (of 68) ClinVar copy-number / structural variants overlap TBCE — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →