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

Summary

fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement (MONDO:0010912) is a disease caused by TUBB3 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TUBB3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 24

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement
Mondo ID	MONDO:0010912
MeSH	C567572
OMIM	600638
DOID	DOID:0081017
UMLS	C2748801
MedGen	412638
GARD	0015321
Is cancer (heuristic)	no

Also known as: CFEOM3A · congenital fibrosis of extraocular muscles caused by mutation in TUBB3 · fibrosis of extraocular muscles, congenital, 3A · fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement · TUBB3 congenital fibrosis of extraocular muscles

Data availability: 24 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › cranial nerve neuropathy › ocular motility disease › congenital fibrosis of extraocular muscles › fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement

Related subtypes (7): fibrosis of extraocular muscles, congenital, 2, fibrosis of extraocular muscles, congenital, 3c, Tukel syndrome, fibrosis of extraocular muscles, congenital, with synergistic divergence, fibrosis of extraocular muscles, congenital, 5, congenital fibrosis of extraocular muscles type 1, fibrosis of extraocular muscles, congenital, 3b

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

24 retrieved; paginated sample, class counts are floors:

7 pathogenic, 6 pathogenic/likely pathogenic, 5 uncertain significance, 2 not provided, 2 conflicting classifications of pathogenicity, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
160191	NM_006086.4(TUBB3):c.292G>A (p.Gly98Ser)	TUBB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
219255	NM_006086.4(TUBB3):c.211G>A (p.Gly71Arg)	TUBB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
219256	NM_006086.4(TUBB3):c.785G>A (p.Arg262His)	TUBB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
219257	NM_006086.4(TUBB3):c.1138C>T (p.Arg380Cys)	TUBB3	Pathogenic	criteria provided, multiple submitters, no conflicts
224784	c.1228G>A	TUBB3	Pathogenic	no assertion criteria provided
265335	NM_006086.4(TUBB3):c.533C>T (p.Thr178Met)	TUBB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372654	NM_006086.4(TUBB3):c.763G>A (p.Val255Ile)	TUBB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
520851	NM_006086.4(TUBB3):c.523G>C (p.Val175Leu)	TUBB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6963	NM_006086.4(TUBB3):c.784C>T (p.Arg262Cys)	TUBB3	Pathogenic	criteria provided, multiple submitters, no conflicts
6964	NM_006086.4(TUBB3):c.904G>A (p.Ala302Thr)	TUBB3	Pathogenic	criteria provided, multiple submitters, no conflicts
6965	NM_006086.4(TUBB3):c.1249G>C (p.Asp417His)	TUBB3	Pathogenic	no assertion criteria provided
6966	NM_006086.4(TUBB3):c.1249G>A (p.Asp417Asn)	TUBB3	Pathogenic	criteria provided, multiple submitters, no conflicts
6967	NM_006086.4(TUBB3):c.1228G>A (p.Glu410Lys)	TUBB3	Pathogenic	criteria provided, multiple submitters, no conflicts
219254	NM_006086.4(TUBB3):c.185G>A (p.Arg62Gln)	TUBB3	Likely pathogenic	criteria provided, single submitter
4277735	NM_006086.4(TUBB3):c.233C>T (p.Ser78Leu)	TUBB3	Likely pathogenic	criteria provided, single submitter
160195	NM_006086.4(TUBB3):c.728C>T (p.Pro243Leu)	TUBB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
438582	NM_006086.4(TUBB3):c.136C>T (p.Arg46Trp)	TUBB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3061833	NM_006086.4(TUBB3):c.229C>T (p.Arg77Cys)	TUBB3	Uncertain significance	criteria provided, single submitter
3068154	NM_006086.4(TUBB3):c.418G>C (p.Gly140Arg)	TUBB3	Uncertain significance	criteria provided, single submitter
3383009	NM_006086.4(TUBB3):c.640A>G (p.Thr214Ala)	TUBB3	Uncertain significance	criteria provided, multiple submitters, no conflicts
4533327	NM_006086.4(TUBB3):c.199G>A (p.Asp67Asn)	TUBB3	Uncertain significance	criteria provided, single submitter
617613	NM_006086.4(TUBB3):c.631T>C (p.Cys211Arg)	TUBB3	Uncertain significance	no assertion criteria provided
1343409	NM_006086.4(TUBB3):c.508G>A (p.Val170Met)	TUBB3	not provided	no classification provided
2505069	NM_006086.4(TUBB3):c.166+4A>C	TUBB3	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TUBB3	Strong	Autosomal dominant	fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TUBB3	Orphanet:300570	Cortical dysgenesis with pontocerebellar hypoplasia due to TUBB3 mutation
TUBB3	Orphanet:45358	Congenital fibrosis of extraocular muscles
TUBB3	Orphanet:467166	Tubulinopathy-associated dysgyria

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TUBB3	HGNC:20772	ENSG00000258947	Q13509	Tubulin beta-3 chain	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TUBB3	Tubulin beta-3 chain	Tubulin is the major constituent of microtubules, protein filaments consisting of alpha- and beta-tubulin heterodimers.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TUBB3	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
embryo	1
ganglionic eminence	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TUBB3	144	ubiquitous	marker	cortical plate, ganglionic eminence, embryo

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TUBB3	6,797

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TUBB3	Q13509	28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 86. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	543.8×	0.016	TUBB3
Transport of connexons to the plasma membrane	1	543.8×	0.016	TUBB3
Gap junction trafficking and regulation	1	475.8×	0.016	TUBB3
Gap junction trafficking	1	475.8×	0.016	TUBB3
Post-chaperonin tubulin folding pathway	1	475.8×	0.016	TUBB3
Formation of tubulin folding intermediates by CCT/TriC	1	423.0×	0.016	TUBB3
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	1	407.9×	0.016	TUBB3
Prefoldin mediated transfer of substrate to CCT/TriC	1	393.8×	0.016	TUBB3
Activation of AMPK downstream of NMDARs	1	380.7×	0.016	TUBB3
RHO GTPases activate IQGAPs	1	346.1×	0.016	TUBB3
Sealing of the nuclear envelope (NE) by ESCRT-III	1	346.1×	0.016	TUBB3
HCMV Infection	1	326.3×	0.016	TUBB3
Chaperonin-mediated protein folding	1	300.5×	0.016	TUBB3
Gap junction assembly	1	292.8×	0.016	TUBB3
Nuclear Envelope (NE) Reassembly	1	292.8×	0.016	TUBB3
Selective autophagy	1	278.5×	0.016	TUBB3
Protein folding	1	259.6×	0.016	TUBB3
Assembly and cell surface presentation of NMDA receptors	1	253.8×	0.016	TUBB3
Cargo trafficking to the periciliary membrane	1	248.3×	0.016	TUBB3
Aggrephagy	1	248.3×	0.016	TUBB3
Carboxyterminal post-translational modifications of tubulin	1	237.9×	0.016	TUBB3
Recycling pathway of L1	1	223.9×	0.016	TUBB3
COPI-independent Golgi-to-ER retrograde traffic	1	207.6×	0.016	TUBB3
Post NMDA receptor activation events	1	203.9×	0.016	TUBB3
Intraflagellar transport	1	200.3×	0.016	TUBB3
Antimicrobial mechanism of IFN-stimulated genes	1	196.9×	0.016	TUBB3
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	193.6×	0.016	TUBB3
Activation of NMDA receptors and postsynaptic events	1	184.2×	0.016	TUBB3
Signaling by Hedgehog	1	184.2×	0.016	TUBB3
Hedgehog ‘off’ state	1	178.4×	0.016	TUBB3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
dorsal root ganglion development	1	3370.4×	0.001	TUBB3
mitotic cell cycle	1	133.8×	0.011	TUBB3
microtubule cytoskeleton organization	1	121.2×	0.011	TUBB3
axon guidance	1	90.6×	0.011	TUBB3

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TUBB3	COLCHICINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TUBB3	21	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	TUBB3
VINBLASTINE	4	TUBB3
LEVOFLOXACIN ANHYDROUS	4	TUBB3
DOCETAXEL	4	TUBB3
NOSCAPINE	4	TUBB3
VINBLASTINE SULFATE	4	TUBB3
PACLITAXEL	4	TUBB3
LEVOFLOXACIN	4	TUBB3
VINORELBINE	4	TUBB3
TIRBANIBULIN	4	TUBB3
PODOFILOX	4	TUBB3
VINCRISTINE	4	TUBB3
DOCETAXEL ANHYDROUS	4	TUBB3
PATUPILONE	3	TUBB3
ABT-751	2	TUBB3
MAYTANSINE	2	TUBB3
DOLASTATIN-10	2	TUBB3
INDIBULIN	2	TUBB3
PARBENDAZOLE	2	TUBB3
NOCODAZOLE	2	TUBB3
COMBRETASTATIN	1	TUBB3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TUBB3	1,781	Binding:1741, Functional:34, ADMET:6

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TUBB3	1,781

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

21 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
COLCHICINE	4	TUBB3
VINBLASTINE	4	TUBB3
LEVOFLOXACIN ANHYDROUS	4	TUBB3
DOCETAXEL	4	TUBB3
NOSCAPINE	4	TUBB3
VINBLASTINE SULFATE	4	TUBB3
PACLITAXEL	4	TUBB3
LEVOFLOXACIN	4	TUBB3
VINORELBINE	4	TUBB3
TIRBANIBULIN	4	TUBB3
PODOFILOX	4	TUBB3
VINCRISTINE	4	TUBB3
DOCETAXEL ANHYDROUS	4	TUBB3
PATUPILONE	3	TUBB3
ABT-751	2	TUBB3
MAYTANSINE	2	TUBB3
DOLASTATIN-10	2	TUBB3
INDIBULIN	2	TUBB3
PARBENDAZOLE	2	TUBB3
NOCODAZOLE	2	TUBB3
COMBRETASTATIN	1	TUBB3

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TUBB3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.