TBCE

protein-coding

tubulin folding cofactor E

Gene summary

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]

Previous symbols:

MANE transcript

NM_003193.5

Inheritance

ClinVar variants

P:65U:148B:161

Top phenotype

Kenny-Caffey syndrome, type 1; Hypoparathyroidism-retardation-dysmorphism syndrome

Max pathogenic AF

—

Genomic locus

chr1:235,367,360-235,452,443

External References & Databases

Ensembl (ENSG00000284770)

Transcript & Mutation Effects

hg38 • Region Span ~85.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044646

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive Kenny-Caffey syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009486

Submitter: Orphanet

hypoparathyroidism-retardation-dysmorphism syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009426

Submitter: Orphanet

encephalopathy, progressive, with amyotrophy and optic atrophyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014968

Submitter: ClinGen

Progressive encephalopathy with amyotrophy and optic atrophy was first linked to biallelic variants of *TBCE* in 2016 (PMID:27666369). Six probands from 4 unrelated Southern Italian families were described as having early onset slowly progressive distal motor neuropathy resembling spinal muscular atrophy with bilateral foot drop, spasticity, cerebellar ataxia and moderate to severe intellectual developmental disorder. Brain MRIs of these patients showed cerebellar atrophy; abnormal iron deposits were also recorded in the older patients. Other reports about a recurrent non-frameshift deletion responsible for the autosomal recessive Kenny-Caffey and Sanjad-Sakati syndromes are not included as they will be lumped in another curation. *TBCE* is required for the folding of a-tubulin, a/b-tubulin dimerization, and subsequent heterodimer polymerization into microtubules, which are major components of the cytoskeleton. Structurally contains a CAP-Gly domain which mediates protein binding to a-tubulin, nine tandemly arranged leucine-rich repeat (LRR) motifs which mediate protein-protein interaction, and a ubiquitin-like domain (UBL) which is implicated in a-tubulin degradation via the proteasome. The mechanism of pathogenicity is thus far associated with two recurrent variants; the homozygous p.Ile155Asn variant or the compound heterozygous c.924del:p.Leu309Ter variant. The gene-disease relationship is also supported by experimental evidence and specifically the mouse model pmn (PMID: 12446740), which is homozygous for the missense variant TBCE:p.Trp524Gly, and shares the same phenotypic features as those observed in affected individuals. In summary, *TBCE* is associated with autosomal recessive progressive encephalopathy with amyotrophy and optic atrophy, seen in 6 individuals. This was approved by the ClinGen Brain Malformation GCEP on 02/25/2025.

encephalopathy, progressive, with amyotrophy and optic atrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014968

Submitter: PanelApp Australia

autosomal recessive Kenny-Caffey syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009486

Submitter: Ambry Genetics

encephalopathy, progressive, with amyotrophy and optic atrophyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014968

Submitter: Ambry Genetics

encephalopathy, progressive, with amyotrophy and optic atrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014968

Submitter: G2P

hypoparathyroidism-retardation-dysmorphism syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009426

Submitter: Labcorp Genetics (formerly Invitae)

hypoparathyroidism-retardation-dysmorphism syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009426

Submitter: G2P

hypoparathyroidism-retardation-dysmorphism syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009426

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Kenny-Caffey syndrome, type 1; Hypoparathyroidism-retardation-dysmorphism syndromeAR

Manifestation: Endocrine; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Endocrine

Rationale: Individuals can present with sequelae of neonatal hypocalcemia, and prompt diagnosis and treatment can lead to correction of electrolyte abnormalities; Some individuals with multiple pituitary anomalies (eg, affecting GH, cortisol, and including features of hypogonadotropic hypogonadism have been described), and surveillance may allow early diagnosis and treatment

Refs: 2843457; 1701077; 2001103; 1308349; 7538982; 9056548; 12389028; 19491227; 19554981; 27666369

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBCE variants in ClinVar

12 Conditions Cataloged

not providedTotal: 479

Inborn genetic diseasesTotal: 74

Hypoparathyroidism-retardation-dysmorphism syndromeTotal: 61

Encephalopathy, progressive, with amyotrophy and optic atrophyTotal: 29

Autosomal recessive Kenny-Caffey syndromeTotal: 23

TBCE-related disorderTotal: 23

not specifiedTotal: 17

Disorder of sexual differentiationTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003193.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			7 clinvar	141 clinvar	2 clinvar	150
missense		3 clinvar	130 clinvar	15 clinvar	2 clinvar	150
nonsense	17 clinvar	3 clinvar				20
start loss			1 clinvar			1
frameshift	25 clinvar	6 clinvar	5 clinvar			36
splice donor/acceptor (+/-2bp)		11 clinvar	5 clinvar	1 clinvar		17
Total	42	23	148	157	4	374

Highest pathogenic variant AF is 0.0000685139

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 86 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003193.5	RefSeq	NP_003184.1	16	MANE Select
ENST00000642610.2	Ensembl	ENSP00000494796.1	16	MANE Select
NM_001079515.3	RefSeq	NP_001072983.1	16	Standard
NM_001287801.2	RefSeq	NP_001274730.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of proteins
Protein folding
Post-chaperonin tubulin folding pathway

Biological Process

microtubule cytoskeleton organization
protein folding
post-chaperonin tubulin folding pathway
mitotic spindle organization

Molecular Function

protein binding
chaperone binding

Cellular Component

cytoplasm
microtubule

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Tubulin-folding protein; involved in the second step of the tubulin folding pathway and in the regulation of tubulin heterodimer dissociation. Required for correct organization of microtubule cytoskeleton and mitotic splindle, and maintenance of the neuronal microtubule network. {ECO:0000269|PubMed:11847227, ECO:0000269|PubMed:27666369}.;
Disease: DISEASE: Hypoparathyroidism-retardation-dysmorphism syndrome (HRDS) [MIM:241410]: An autosomal recessive multisystem disorder characterized by hypoparathyroidism, intrauterine and postnatal growth retardation, psychomotor retardation, epilepsy, microcephaly, and facial dysmorphism. {ECO:0000269|PubMed:12389028}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Kenny-Caffey syndrome 1 (KCS1) [MIM:244460]: An autosomal recessive form of Kenny-Caffey syndrome, a disorder characterized by impaired skeletal development with small and dense bones, short stature, and primary hypoparathyroidism with hypocalcemia. Clinical features include cortical thickening and medullary stenosis of the tubular bones, delayed closure of fontanels, defective dentition, small eyes with hypermetropia, and frontal bossing with a triangular face. {ECO:0000269|PubMed:12389028}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Encephalopathy, progressive, with amyotrophy and optic atrophy (PEAMO) [MIM:617207]: An autosomal recessive, progressive, neurodegenerative encephalopathy with onset in infancy. Affected individuals manifest delayed psychomotor development, severe hypotonia, motor regression, spinal muscular atrophy, distal amyotrophy and weakness of all limbs, and intellectual disability of variable severity. Additional features include optic atrophy, thin corpus callosum, and cerebellar atrophy. {ECO:0000269|PubMed:27666369}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.348

Intolerance Scores

LoFtool: 0.901
RVIS EVS: 0.8
RVIS percentile EVS: 87.66

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.281

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium