TBCD

protein-coding

tubulin folding cofactor D, the group of Armadillo like helical domain containing

Gene summary

Cofactor D 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. [provided by RefSeq, Jul 2008]

MANE transcript

NM_005993.5

Inheritance

ClinVar variants

P:108U:306B:481

Top phenotype

Early-onset progressive encephalopathy with brain atrophy and thin corpus callosum (PEBAT)

gnomAD constraint

pLI —, LoF o/e 0.36

Max pathogenic AF

—

Genomic locus

chr17:82,752,042-82,945,914

External References & Databases

Ensembl (ENSG00000141556)

Transcript & Mutation Effects

hg38 • Region Span ~193.9 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 syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044646

Submitter: Orphanet

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

Inheritance Pattern: AR

Disease ID:MONDO:0044646

Submitter: Labcorp Genetics (formerly Invitae)

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

Inheritance Pattern: AR

Disease ID:MONDO:0044646

Submitter: ClinGen

TBCD was first reported in relation to early-onset neurodegenerative encephalopathy in 2016 (Miyake et al., PMID: 27666374). The clinical presentation includes intellectual disability with developmental regression, seizures, hypotonia, spasticity, and secondary microcephaly; brain imaging shows cerebral and cerebellar atrophy, thin corpus callosum, and secondary hypomyelination. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability, therefore, the following disease entities have been lumped into one disease entity: early onset progressive encephalopathy with brain atrophy and thin corpus callosum (PEBAT) (OMIM:617193), early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (http://purl.obolibrary.org/obo/MONDO_0044646, ORPHA:496641). Twenty different variants (15 missense, 2 nonsense, 3 splice-disrupting) that have been reported in 15 probands in 6 publications (PMIDs: 27666374, 27666370, 28158450, 27807845, 29921875, 34423067) are included in this curation. More evidence is available in the literature (PMIDs: 27928163, 31240573, 31569255, 34943336, 36527993) but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease association is also supported by experimental evidence including functional assays demonstrating co-immunoprecipitation with TBCE, ARL2, and beta tubulin (PMID 27666374), expression evidence demonstrating decreased levels of TBCD in fibroblasts of affected individuals (PMID 27666370), functional assays demonstrating perturbations in cell proliferation and migration in mouse brain lysates with shRNA-mediated suppression of TBCD (PMID 28158450) and a morpholino-mediated TBCD knockdown in zebrafish that recapitulated some pathological features of the human disease (PMID 27807845). In summary, TBCD is definitively associated with autosomal recessive TBCD-related early-onset neurodegenerative encephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Brain Malformations gene curation expert panel on 13Mar2025.

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

Inheritance Pattern: AR

Disease ID:MONDO:0044646

Submitter: G2P

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

Inheritance Pattern: AR

Disease ID:MONDO:0044646

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Early-onset progressive encephalopathy with brain atrophy and thin corpus callosum (PEBAT)AR

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 27666370; 27666374

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBCD variants in ClinVar

11 Conditions Cataloged

not providedTotal: 1167

Inborn genetic diseasesTotal: 188

not specifiedTotal: 167

Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndromeTotal: 110

TBCD-related disorderTotal: 34

ZNF750-related disorderTotal: 7

Seborrhea-like dermatitis with psoriasiform elementsTotal: 5

See casesTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005993.5. 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		1 clinvar	3 clinvar	414 clinvar	14 clinvar	432
missense	5 clinvar	17 clinvar	287 clinvar	48 clinvar	4 clinvar	361
nonsense	21 clinvar	6 clinvar	4 clinvar			31
start loss						0
frameshift	23 clinvar	10 clinvar	1 clinvar			34
splice donor/acceptor (+/-2bp)	2 clinvar	23 clinvar	11 clinvar		1 clinvar	37
Total	51	57	306	462	19	895

Highest pathogenic variant AF is 0.00005705101

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 136 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005993.5	RefSeq	NP_005984.3	39	MANE Select
ENST00000355528.9	Ensembl	ENSP00000347719.4	39	MANE Select
NM_001411101.1	RefSeq	NP_001398030.1	38	Standard
NM_001411102.1	RefSeq	NP_001398031.1	38	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tbcd	Danio rerio	Structure: muscle cell Quality: disorganized abnormal

Gene / Model

Organism

Observed Phenotype

tbcd

Danio rerio

Structure: muscle cell

Quality: disorganized

abnormal

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
mitotic cell cycle
protein folding
tubulin complex assembly
post-chaperonin tubulin folding pathway

Molecular Function

GTPase activator activity
protein binding
beta-tubulin binding
chaperone binding

Cellular Component

cytoplasm
centrosome
microtubule
adherens junction
bicellular tight junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000355528
Coding exons: 39
Length: 190785
Individuals with no LoFs: 124866
Homozygous LoFs: 0
Heterozygous LoFs: 67
Defined: 124933
p: 0.000268

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.82	573	710	0.807	0.0000452	7659
Missense (PolyPhen)		144	225.85	0.6376		2396
Synonymous	-0.177	303	299	1.01	0.0000216	2344
Loss of Function	5.11	26	73.1	0.356	0.00000391	804

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00013	rare
Latino/Admixed American	0.00076	0.00075	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00017	0.00017	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00023	0.00022	rare
South Asian	0.00030	0.00029	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Tubulin-folding protein implicated in the first step of the tubulin folding pathway and required for tubulin complex assembly. Involved in the regulation of microtubule polymerization or depolymerization, it modulates microtubule dynamics by capturing GTP-bound beta-tubulin (TUBB). Its ability to interact with beta tubulin is regulated via its interaction with ARL2. Acts as a GTPase-activating protein (GAP) for ARL2. Induces microtubule disruption in absence of ARL2. Increases degradation of beta tubulin, when overexpressed in polarized cells. Promotes epithelial cell detachment, a process antagonized by ARL2. Induces tight adherens and tight junctions disassembly at the lateral cell membrane (PubMed:10722852, PubMed:10831612, PubMed:11847227, PubMed:20740604, PubMed:27666370, PubMed:28158450). Required for correct assembly and maintenance of the mitotic spindle, and proper progression of mitosis (PubMed:27666370). Involved in neuron morphogenesis (PubMed:27666374). {ECO:0000269|PubMed:10722852, ECO:0000269|PubMed:10831612, ECO:0000269|PubMed:11847227, ECO:0000269|PubMed:20740604, ECO:0000269|PubMed:27666370, ECO:0000269|PubMed:27666374, ECO:0000269|PubMed:28158450}.;
Disease: DISEASE: Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum (PEBAT) [MIM:617193]: An autosomal recessive disease with neurodevelopmental and neurodegenerative features. PEBAT is characterized by early-onset cortical atrophy, hypomyelination, microcephaly, thin corpus callosum, delayed psychomotor development, developmental regression, intellectual disability, seizures, optic atrophy, muscle weakness and atrophy, spastic quadriplegia, and respiratory insufficiency due to hypotonia. {ECO:0000269|PubMed:27666370, ECO:0000269|PubMed:27666374, ECO:0000269|PubMed:27807845, ECO:0000269|PubMed:28158450}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.110

Intolerance Scores

LoFtool: 0.799
RVIS EVS: -1.45
RVIS percentile EVS: 3.89

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.842

Gene Damage Prediction

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