TUBB3

protein-coding

tubulin beta 3 class III, the group of Tubulins

Gene summary

This gene encodes a class III member of the beta tubulin protein family. Beta tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. This protein is primarily expressed in neurons and may be involved in neurogenesis and axon guidance and maintenance. Mutations in this gene are the cause of congenital fibrosis of the extraocular muscles type 3. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 6. [provided by RefSeq, Oct 2010]

Previous symbols:

FEOM3

MANE transcript

NM_006086.4

Inheritance

AD, AR

ClinVar variants

P:73U:175B:111

Top phenotype

Cortical dysplasia, complex, with other brain malformations 1; Fibrosis of extraocular muscles, congenital, 3A

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr16:89,921,392-89,938,761

External References & Databases

Ensembl (ENSG00000258947)

Transcript & Mutation Effects

hg38 • Region Span ~17.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex cortical dysplasia with other brain malformations 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013541

Submitter: PanelApp Australia

complex cortical dysplasia with other brain malformations 1SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013541

Submitter: Orphanet

TUBB3-related tubulinopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100154

Submitter: ClinGen

*TUBB3* encodes neuron-specific β-tubulin isotype III which is the most dynamic tubulin within the β-tubulin family (PMID: 20074521). *TUBB3* was first reported in relation to tubulopathies in 2010 (Tischfield et al., PMID: 20074521). *TUBB3*-related tubulinopathy is characterized by malformations of cortical development, axon guidance defects, white matter abnormalities, and/or congenital fibrosis of the extraocular muscles (CFEOM) due to heterozygous *de novo* or inherited variants with high penetrance. Individuals may present with variable combinations of malformations of cortical development, dysplasia of the basal ganglia, brainstem, and/or cerebellum, CFEOM, additional cranial nerve involvement, Kallmann syndrome, cyclic vomiting, peripheral neuropathy, and/or contractures. Developmental delays, intellectual disability, ocular motor apraxia, and mirror movements are also frequent features. Multiple missense variants, most of which were *de novo*, reported in over 20 probands across 12 publications (PMIDs: 20829227, 26639658, 34562182, 20074521, 28503613, 26130693, 28299356, 34863918, 29187032, 34869359, 26739025, 32573066) and one additional proband from the Brain Gene Registry (braingeneregistry.wustl.edu; ClinVar ID: SCV002103326.1) are included in this curation. This gene-disease relationship is also supported by experimental evidence. *TUBB3* is within the β-tubulin family with the genes *TUBB2A* and *TUBB2B* which have been definitively implicated in conditions (tubulinopathy and complex cortical dysplasia with other brain malformations, respectively) with overlapping phenotypes (PMID: 35915025). Additionally, a R262C knock-in mouse model showed defects in the guidance of axons throughout the brain and a thinning of the anterior commissure similar to human patients (PMID: 20074521). Lastly, cells with the variants R262C, A302T, R62Q, and R380C demonstrated increases in microtubule stabilization and increased time in “paused” states compared to wild-type (PMID: 20074521). The mechanism of pathogenicity appears to be gain-of-function (PMID: 20074521). In summary, there is definitive evidence supporting the relationship between *TUBB3* and autosomal dominant TUBB3-related tubulinopathy. 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 Intellectual Disability and Autism GCEP on September 8, 2022 (SOP 9).

fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvementSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010912

Submitter: Labcorp Genetics (formerly Invitae)

complex cortical dysplasia with other brain malformations 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013541

Submitter: Illumina

congenital fibrosis of extraocular musclesSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007614

Submitter: Orphanet

fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvementSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010912

Submitter: PanelApp Australia

tubulinopathy-associated dysgyriaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018763

Submitter: Orphanet

complex cortical dysplasia with other brain malformations 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013541

Submitter: G2P

complex cortical dysplasia with other brain malformations 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013541

Submitter: Labcorp Genetics (formerly Invitae)

fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvementSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010912

Submitter: Genomics England PanelApp

fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvementSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010912

Submitter: G2P

Clinical Genomic Database (CGD)

Cortical dysplasia, complex, with other brain malformations 1; Fibrosis of extraocular muscles, congenital, 3AAD/AR

Manifestation: Musculoskeletal; 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: 7724178; 10393037; 12073023; 20829227; 20074521

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TUBB3 variants in ClinVar

25 Conditions Cataloged

not providedTotal: 299

Complex cortical dysplasia with other brain malformations 1Total: 59

not specifiedTotal: 55

TUBB3-related disorderTotal: 44

Fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvementTotal: 29

Inborn genetic diseasesTotal: 24

TUBB3-related tubulinopathyTotal: 8

Abnormal cerebral morphologyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006086.4. 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			5 clinvar	96 clinvar	3 clinvar	104
missense	15 clinvar	58 clinvar	162 clinvar	9 clinvar	3 clinvar	247
nonsense			6 clinvar			6
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	15	58	175	105	6	359

Highest pathogenic variant AF is 0.0000065713384

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006086.4	RefSeq	NP_006077.2	4	MANE Select
ENST00000315491.12	Ensembl	ENSP00000320295.7	4	MANE Select
NM_001197181.2	RefSeq	NP_001184110.1	2	Standard
ENST00000553656.5	Ensembl	ENSP00000452001.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Phagosome - Homo sapiens (human)
Gap junction - Homo sapiens (human)
Pathogenic Escherichia coli infection - Homo sapiens (human)
Pathogenic Escherichia coli infection
Parkin-Ubiquitin Proteasomal System pathway

Biological Process

microtubule cytoskeleton organization
mitotic cell cycle
microtubule-based process
axon guidance
neuron differentiation

Molecular Function

GTPase activity
structural constituent of cytoskeleton
protein binding
GTP binding

Cellular Component

nucleus
cytoplasm
microtubule
axon
dendrite

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000315491
Coding exons: 4
Length: 17370
Individuals with no LoFs: 125709
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125712
p: 0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.58	77	300	0.256	0.0000234	2991
Missense (PolyPhen)		14	123.86	0.11303		1323
Synonymous	-2.22	172	139	1.24	0.0000130	879
Loss of Function	3.36	1	15.0	0.0665	7.29e-7	163

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain. TUBB3 plays a critical role in proper axon guidance and mantainance. {ECO:0000269|PubMed:20074521}.;
Disease: DISEASE: Fibrosis of extraocular muscles, congenital, 3A (CFEOM3A) [MIM:600638]: A congenital ocular motility disorder marked by restrictive ophthalmoplegia affecting extraocular muscles innervated by the oculomotor and/or trochlear nerves. It is clinically characterized by anchoring of the eyes in downward gaze, ptosis, and backward tilt of the head. Congenital fibrosis of extraocular muscles type 3 presents as a non-progressive, autosomal dominant disorder with variable expression. Patients may be bilaterally or unilaterally affected, and their oculo-motility defects range from complete ophthalmoplegia (with the eyes fixed in a hypo- and exotropic position), to mild asymptomatic restrictions of ocular movement. Ptosis, refractive error, amblyopia, and compensatory head positions are associated with the more severe forms of the disorder. In some cases, the ocular phenotype is accompanied by additional features including developmental delay, corpus callosum agenesis, basal ganglia dysmorphism, facial weakness, polyneuropathy. {ECO:0000269|PubMed:20074521}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cortical dysplasia, complex, with other brain malformations 1 (CDCBM1) [MIM:614039]: A disorder of aberrant neuronal migration and disturbed axonal guidance. Affected individuals have mild to severe mental retardation, strabismus, axial hypotonia, and spasticity. Brain imaging shows variable malformations of cortical development, including polymicrogyria, gyral disorganization, and fusion of the basal ganglia, as well as thin corpus callosum, hypoplastic brainstem, and dysplastic cerebellar vermis. Extraocular muscles are not involved. {ECO:0000269|PubMed:20829227}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.701

Intolerance Scores

LoFtool: 0.244
RVIS EVS: -0.76
RVIS percentile EVS: 13.33

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.927

Gene Damage Prediction

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