3-methylglutaconic aciduria type 3

Summary

3-methylglutaconic aciduria type 3 (MONDO:0009787) is a disease caused by OPA3 (GenCC Definitive), with 5 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: OPA3 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 571
• Phenotypes (HPO): 9

Clinical features

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0000505	Visual impairment	Very frequent (80-99%)
HP:0001266	Choreoathetosis	Very frequent (80-99%)
HP:0003535	3-Methylglutaconic aciduria	Very frequent (80-99%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0002313	Spastic paraparesis	Frequent (30-79%)
HP:0001288	Gait disturbance	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	3-methylglutaconic aciduria type 3
Mondo ID	MONDO:0009787
MeSH	C535311
OMIM	258501
Orphanet	67047
DOID	DOID:0110004
ICD-11	535412248
SNOMED CT	297232009
UMLS	C0574084
MedGen	108273
GARD	0005663
Is cancer (heuristic)	no

Also known as: 3-alpha methylglutaconic aciduria type III · 3-methylglutaconic aciduria caused by mutation in OPA3 · 3-methylglutaconic aciduria, type III · autosomal recessive optic atrophy plus syndrome · autosomal recessive optic atrophy type 3 · Costeff optic atrophy syndrome · Costeff syndrome · infantile optic atrophy with chorea and spastic paraplegia · Iraqi Jewish optic atrophy plus · MGA type III · MGA3 · MGCA3 · OPA3 3-methylglutaconic aciduria · OPA3 defect · optic atrophy infantile with chorea and spastic paraplegia

Data availability: 571 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn organic aciduria › classic organic aciduria › 3-methylglutaconic aciduria › 3-methylglutaconic aciduria type 3

Related subtypes (9): 3-methylglutaconic aciduria type 1, 3-methylglutaconic aciduria type 4, Barth syndrome, 3-methylglutaconic aciduria type 5, 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, 3-methylglutaconic aciduria, type VIIB, 3-methylglutaconic aciduria type 8, 3-methylglutaconic aciduria type 9, 3-methylglutaconic aciduria, type VIIA

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

571 retrieved; paginated sample, class counts are floors:

275 uncertain significance, 152 likely benign, 56 conflicting classifications of pathogenicity, 27 benign, 26 likely pathogenic, 18 benign/likely benign, 12 pathogenic, 3 pathogenic/likely pathogenic, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
937620	NM_145261.4(DNAJC19):c.63C>G (p.Tyr21Ter)	DNAJC19	Pathogenic	criteria provided, single submitter
3754912	NM_025136.4(OPA3):c.39C>G (p.Tyr13Ter)	LOC130064709	Pathogenic	criteria provided, single submitter
5082	NM_130837.3(OPA1):c.2873_2876del	OPA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1727235	NM_025136.4(OPA3):c.143-1G>A	OPA3	Pathogenic	criteria provided, multiple submitters, no conflicts
2128878	NM_025136.4(OPA3):c.103G>T (p.Glu35Ter)	OPA3	Pathogenic	criteria provided, single submitter
21710	NM_025136.4(OPA3):c.415C>T (p.Gln139Ter)	OPA3	Pathogenic/Likely pathogenic	no assertion criteria provided
3248433	NC_000019.9:g.(?46056772)(46088022_?)del	OPA3	Pathogenic	criteria provided, single submitter
3775723	NM_025136.4(OPA3):c.55del (p.Val19fs)	OPA3	Pathogenic	criteria provided, single submitter
4239	NM_025136.4(OPA3):c.143-1G>C	OPA3	Pathogenic	criteria provided, multiple submitters, no conflicts
4241	NM_025136.4(OPA3):c.313C>G (p.Gln105Glu)	OPA3	Pathogenic	criteria provided, multiple submitters, no conflicts
4242	NM_025136.4(OPA3):c.322_339del (p.Gln108_Glu113del)	OPA3	Pathogenic	no assertion criteria provided
620409	NM_025136.4(OPA3):c.52C>T (p.Gln18Ter)	OPA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
831267	NC_000019.10:g.(?45584613)(45584774_?)del	OPA3	Pathogenic	criteria provided, single submitter
918005	NM_025136.4(OPA3):c.32T>A (p.Leu11Gln)	OPA3	Pathogenic	no assertion criteria provided
952107	NM_025136.4(OPA3):c.143-2_143-1delinsCC	OPA3	Pathogenic	criteria provided, single submitter
2677424	NM_025136.4(OPA3):c.45del (p.Ile16fs)	LOC130064709	Likely pathogenic	criteria provided, single submitter
1067581	NM_025136.4(OPA3):c.1A>G (p.Met1Val)	OPA3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324830	NM_025136.4(OPA3):c.194del (p.Gly65fs)	OPA3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1723421	NC_000019.9:g.(46057170_46087880)(46088123?)del	OPA3	Likely pathogenic	criteria provided, single submitter
2190228	NM_025136.4(OPA3):c.152G>A (p.Trp51Ter)	OPA3	Likely pathogenic	criteria provided, single submitter
2677419	NM_025136.4(OPA3):c.217G>T (p.Glu73Ter)	OPA3	Likely pathogenic	criteria provided, single submitter
2677421	NM_025136.4(OPA3):c.97C>T (p.Arg33Ter)	OPA3	Likely pathogenic	criteria provided, single submitter
2677422	NM_025136.4(OPA3):c.227dup (p.Ala77fs)	OPA3	Likely pathogenic	criteria provided, single submitter
2677423	NM_025136.4(OPA3):c.287del (p.Cys96fs)	OPA3	Likely pathogenic	criteria provided, single submitter
3239998	NM_025136.4(OPA3):c.82_84delinsT (p.Ile27_Lys28insTer)	OPA3	Likely pathogenic	criteria provided, single submitter
3239999	NM_025136.4(OPA3):c.411_422delinsC (p.Gln137fs)	OPA3	Likely pathogenic	criteria provided, single submitter
3248434	NC_000019.9:g.(?46056772)(46057189_?)del	OPA3	Likely pathogenic	criteria provided, single submitter
3583954	NM_025136.4(OPA3):c.308_312del (p.Arg103fs)	OPA3	Likely pathogenic	criteria provided, single submitter
370448	NM_025136.4(OPA3):c.539A>G (p.Ter180Trp)	OPA3	Likely pathogenic	no assertion criteria provided
3760447	NM_025136.4(OPA3):c.140A>G (p.Gln47Arg)	OPA3	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 12 · 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
OPA3	Definitive	Autosomal recessive	3-methylglutaconic aciduria type 3	9
MICOS13	Supportive	Autosomal recessive	3-methylglutaconic aciduria type 3	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
OPA3	Orphanet:67036	Autosomal dominant optic atrophy and cataract
OPA3	Orphanet:67047	3-methylglutaconic aciduria type 3
MICOS13	Orphanet:67047	3-methylglutaconic aciduria type 3
MED12	Orphanet:1415	Hardikar syndrome
MED12	Orphanet:293707	Blepharophimosis-intellectual disability syndrome, MKB type
MED12	Orphanet:776	Lujan-Fryns syndrome
MED12	Orphanet:777	X-linked non-syndromic intellectual disability
MED12	Orphanet:93932	FG syndrome type 1
DNAJC19	Orphanet:66634	Dilated cardiomyopathy with ataxia
OPA1	Orphanet:1215	Autosomal dominant optic atrophy plus syndrome
OPA1	Orphanet:1239	Behr syndrome
OPA1	Orphanet:98673	Autosomal dominant optic atrophy, classic form

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
OPA3	HGNC:8142	ENSG00000125741	Q9H6K4	Optic atrophy 3 protein	gencc,clinvar
MICOS13	HGNC:33702	ENSG00000174917	Q5XKP0	MICOS complex subunit MIC13	gencc
MED12	HGNC:11957	ENSG00000184634	Q93074	Mediator of RNA polymerase II transcription subunit 12	clinvar
DNAJC19	HGNC:30528	ENSG00000205981	Q96DA6	Mitochondrial import inner membrane translocase subunit TIM14	clinvar
OPA1	HGNC:8140	ENSG00000198836	O60313	Dynamin-like GTPase OPA1, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
OPA3	Optic atrophy 3 protein	May play some role in mitochondrial processes.
MICOS13	MICOS complex subunit MIC13	Component of the MICOS complex, a large protein complex of the mitochondrial inner membrane that plays crucial roles in the maintenance of crista junctions, inner membrane architecture, and formation of contact sites to the outer membrane.
MED12	Mediator of RNA polymerase II transcription subunit 12	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
DNAJC19	Mitochondrial import inner membrane translocase subunit TIM14	Mitochondrial co-chaperone which forms a complex with prohibitins to regulate cardiolipin remodeling.
OPA1	Dynamin-like GTPase OPA1, mitochondrial	Dynamin-related GTPase that is essential for normal mitochondrial morphology by mediating fusion of the mitochondrial inner membranes, regulating cristae morphology and maintaining respiratory chain function.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.2

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
Enzyme (other)	1	2.4×	0.353
Other/Unknown	4	1.4×	0.353

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
OPA3	Other/Unknown	no		OPA3-like
MICOS13	Other/Unknown	no		Mic13
MED12	Other/Unknown	no		Mediator_Med12, Mediator_Med12_catenin-bd, Mediator_Med12_LCEWAV
DNAJC19	Other/Unknown	no		DnaJ_domain, J_dom_sf
OPA1	Enzyme (other)	yes	3.6.5.5	Dynamin_GTPase, Dynamin, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

4 cohort genes 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	2
tendon of biceps brachii	2
calcaneal tendon	2
hindlimb stylopod muscle	1
left testis	1
right atrium auricular region	1
left ovary	1
right adrenal gland	1
right adrenal gland cortex	1
tendon	1
adrenal tissue	1
endothelial cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
OPA3	213	ubiquitous	yes	tendon of biceps brachii, hindlimb stylopod muscle, apex of heart
MICOS13	254	ubiquitous	marker	apex of heart, left testis, right atrium auricular region
MED12	281	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left ovary
DNAJC19	256	ubiquitous	marker	tendon of biceps brachii, tendon, calcaneal tendon
OPA1	288	ubiquitous	marker	adrenal tissue, calcaneal tendon, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MED12	3,322
OPA1	2,630
DNAJC19	2,167
MICOS13	1,501
OPA3	87

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
OPA1	O60313	11
MED12	Q93074	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNAJC19	Q96DA6	87.50
MICOS13	Q5XKP0	86.01
OPA3	Q9H6K4	83.13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of Apoptosis	1	475.8×	0.055	OPA1
Cristae formation	1	86.5×	0.066	MICOS13
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	53.9×	0.066	MED12
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	49.2×	0.066	MED12
Respiratory Syncytial Virus Infection Pathway	1	49.2×	0.066	MED12
Mitochondrial protein import	1	42.0×	0.066	DNAJC19
Mitochondrial biogenesis	1	42.0×	0.066	MICOS13
RSV-host interactions	1	39.1×	0.066	MED12
Adipogenesis	1	39.1×	0.066	MED12
Epigenetic regulation by WDR5-containing histone modifying complexes	1	38.6×	0.066	MED12
Regulation of lipid metabolism by PPARalpha	1	35.2×	0.066	MED12
Transcriptional regulation of white adipocyte differentiation	1	32.4×	0.066	MED12
Mitochondrial protein degradation	1	28.6×	0.069	OPA1
PPARA activates gene expression	1	23.6×	0.077	MED12
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	20.7×	0.082	MED12
Epigenetic regulation of gene expression	1	17.8×	0.089	MED12
Organelle biogenesis and maintenance	1	16.5×	0.091	MICOS13
Metabolism of lipids	1	7.9×	0.169	MED12
Viral Infection Pathways	1	7.7×	0.169	MED12
Infectious disease	1	6.2×	0.197	MED12
RNA Polymerase II Transcription	1	5.6×	0.206	MED12
Gene expression (Transcription)	1	4.5×	0.244	MED12
Generic Transcription Pathway	1	3.8×	0.270	MED12
Developmental Biology	1	3.6×	0.270	MED12
Disease	1	3.3×	0.283	MED12
Metabolism	1	2.9×	0.302	MED12

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cristae formation	2	421.3×	3e-04	MICOS13, OPA1
inner mitochondrial membrane organization	2	337.0×	3e-04	MICOS13, OPA1
visual perception	3	47.7×	3e-04	OPA3, DNAJC19, OPA1
mitochondrial inner membrane fusion	1	3370.4×	0.003	OPA1
neural tube closure	2	74.9×	0.003	MED12, OPA1
mitochondrion organization	2	60.7×	0.003	OPA3, OPA1
regulation of cardiolipin metabolic process	1	1685.2×	0.004	DNAJC19
axis elongation involved in somitogenesis	1	1123.5×	0.005	MED12
membrane tubulation	1	1123.5×	0.005	OPA1
positive regulation of T-helper 17 cell lineage commitment	1	421.3×	0.011	OPA1
embryonic neurocranium morphogenesis	1	374.5×	0.011	MED12
genitalia development	1	337.0×	0.011	DNAJC19
peroxisome fission	1	306.4×	0.012	OPA1
axonal transport of mitochondrion	1	280.9×	0.012	OPA1
GTP metabolic process	1	224.7×	0.013	OPA1
mitochondrial fission	1	210.7×	0.013	OPA1
Schwann cell development	1	210.7×	0.013	MED12
regulation of growth	1	187.2×	0.013	OPA3
mitochondrial fusion	1	168.5×	0.013	OPA1
negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	1	168.5×	0.013	OPA1
negative regulation of release of cytochrome c from mitochondria	1	160.5×	0.013	OPA1
embryonic brain development	1	160.5×	0.013	MED12
post-anal tail morphogenesis	1	146.5×	0.014	MED12
protein import into mitochondrial matrix	1	140.4×	0.014	DNAJC19
protein complex oligomerization	1	134.8×	0.014	OPA1
endoderm development	1	124.8×	0.014	MED12
oligodendrocyte development	1	120.4×	0.014	MED12
positive regulation of interleukin-17 production	1	120.4×	0.014	OPA1
obsolete protein targeting to mitochondrion	1	116.2×	0.014	DNAJC19
neuromuscular process	1	105.3×	0.014	OPA3

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 3

Druggability breadth: 3 of 5 evidence-associated genes (60%) 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
OPA1	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
OPA1	2	4
MED12	1	2
OPA3	0	0
MICOS13	0	0
DNAJC19	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	OPA1
TIVANTINIB	3	OPA1
MOLIBRESIB	2	MED12

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MED12	6	Binding:6
OPA1	2	Binding:2
MICOS13	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
OPA1	3.6.5.5	dynamin GTPase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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)
MOMELOTINIB	4	OPA1
TIVANTINIB	3	OPA1
MOLIBRESIB	2	MED12

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	OPA1
B	Phased (≥1) drug, not yet approved	1	MED12
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	OPA3, MICOS13, DNAJC19

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
OPA3	0	—
MICOS13	1	—
DNAJC19	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.