3-methylglutaconic aciduria type 5

Summary

3-methylglutaconic aciduria type 5 (MONDO:0012435) is a disease caused by DNAJC19 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: DNAJC19 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 139
• Phenotypes (HPO): 37
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

37 HPO clinical features (Orphanet curated; top 37 by frequency):

HPO ID	Term	Frequency
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0001644	Dilated cardiomyopathy	Very frequent (80-99%)
HP:0003530	Glutaric acidemia	Very frequent (80-99%)
HP:0003535	3-Methylglutaconic aciduria	Very frequent (80-99%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001657	Prolonged QT interval	Frequent (30-79%)
HP:0002151	Increased circulating lactate concentration	Frequent (30-79%)
HP:0002194	Delayed gross motor development	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0004840	Hypochromic microcytic anemia	Frequent (30-79%)
HP:0004856	Normochromic microcytic anemia	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0000051	Perineal hypospadias	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001414	Microvesicular hepatic steatosis	Occasional (5-29%)
HP:0001998	Neonatal hypoglycemia	Occasional (5-29%)
HP:0008689	Bilateral cryptorchidism	Occasional (5-29%)
HP:0008736	Hypoplasia of penis	Occasional (5-29%)
HP:0011623	Muscular ventricular septal defect	Occasional (5-29%)
HP:0000821	Hypothyroidism	Very rare (<1-4%)
HP:0001319	Neonatal hypotonia	Very rare (<1-4%)
HP:0001324	Muscle weakness	Very rare (<1-4%)
HP:0001332	Dystonia	Very rare (<1-4%)
HP:0001999	Abnormal facial shape	Very rare (<1-4%)
HP:0002061	Lower limb spasticity	Very rare (<1-4%)
HP:0002345	Action tremor	Very rare (<1-4%)
HP:0002376	Developmental regression	Very rare (<1-4%)
HP:0003700	Generalized amyotrophy	Very rare (<1-4%)
HP:0007146	Bilateral basal ganglia lesions	Very rare (<1-4%)
HP:0007366	Atrophy/Degeneration affecting the brainstem	Very rare (<1-4%)
HP:0008619	Bilateral sensorineural hearing impairment	Very rare (<1-4%)
HP:0008762	Repetitive compulsive behavior	Very rare (<1-4%)
HP:0009110	Diaphragmatic eventration	Very rare (<1-4%)
HP:0100660	Dyskinesia	Very rare (<1-4%)
HP:0100702	Arachnoid cyst	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	3-methylglutaconic aciduria type 5
Mondo ID	MONDO:0012435
MeSH	C565706
OMIM	610198
Orphanet	66634
DOID	DOID:0110000
ICD-11	422277813
NCIT	C173146
SNOMED CT	711412004
UMLS	C1857776
MedGen	347542
GARD	0012964
Is cancer (heuristic)	no

Also known as: 3 alpha methylglutaconic aciduria type V · 3 methylglutaconic aciduria type V · 3-methylglutaconic aciduria caused by mutation in DNAJC19 · 3-methylglutaconic aciduria type 5 · 3-methylglutaconic aciduria type V · 3-METHYLGLUTACONIC aciduria, type V · DCMA · DCMA syndrome · dilated cardiomyopathy with ataxia · DNAJC19 3-methylglutaconic aciduria · MGA 5 · MGA V · MGA5 · MGCA5

Data availability: 139 ClinVar variants · 3 GenCC gene-disease records · 4 cell lines.

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 5

Related subtypes (9): 3-methylglutaconic aciduria type 1, 3-methylglutaconic aciduria type 4, 3-methylglutaconic aciduria type 3, Barth syndrome, 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

139 retrieved; paginated sample, class counts are floors:

64 likely benign, 42 uncertain significance, 13 pathogenic, 7 likely pathogenic, 5 conflicting classifications of pathogenicity, 3 benign/likely benign, 3 benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
120181	NM_145261.4(DNAJC19):c.300del (p.Ala101fs)	DNAJC19	Pathogenic	no assertion criteria provided
1299515	NM_145261.4(DNAJC19):c.62dup (p.Tyr21Ter)	DNAJC19	Pathogenic	criteria provided, multiple submitters, no conflicts
1324286	NM_145261.4(DNAJC19):c.63del (p.Arg20_Tyr21insTer)	DNAJC19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1349917	NM_145261.4(DNAJC19):c.55+1G>A	DNAJC19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1460139	NC_000003.11:g.(?180707368)(180707390_?)del	DNAJC19	Pathogenic	criteria provided, single submitter
1951	NM_145261.4(DNAJC19):c.130-1G>C	DNAJC19	Pathogenic	criteria provided, multiple submitters, no conflicts
2157602	NM_145261.4(DNAJC19):c.250C>T (p.Arg84Ter)	DNAJC19	Pathogenic	criteria provided, single submitter
2427336	NC_000003.11:g.(?180332709)(180707390_?)del	DNAJC19	Pathogenic	criteria provided, single submitter
3069178	NM_145261.4(DNAJC19):c.102del (p.Lys34fs)	DNAJC19	Pathogenic	criteria provided, single submitter
3646339	NM_145261.4(DNAJC19):c.122del (p.Pro41fs)	DNAJC19	Pathogenic	criteria provided, single submitter
3676557	NM_145261.4(DNAJC19):c.168dup (p.Lys57fs)	DNAJC19	Pathogenic	criteria provided, single submitter
3688402	NM_145261.4(DNAJC19):c.263del (p.Leu87_Leu88insTer)	DNAJC19	Pathogenic	criteria provided, single submitter
4760020	NM_145261.4(DNAJC19):c.29_32del (p.Leu10fs)	DNAJC19	Pathogenic	criteria provided, single submitter
937620	NM_145261.4(DNAJC19):c.63C>G (p.Tyr21Ter)	DNAJC19	Pathogenic	criteria provided, single submitter
958162	NM_145261.4(DNAJC19):c.51del (p.Phe17fs)	DNAJC19	Pathogenic	criteria provided, single submitter
1691439	NM_145261.4(DNAJC19):c.129+1G>A	DNAJC19	Likely pathogenic	criteria provided, single submitter
235279	NM_145261.4(DNAJC19):c.4-1G>A	DNAJC19	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2717499	NM_145261.4(DNAJC19):c.280+1_280+5del	DNAJC19	Likely pathogenic	criteria provided, single submitter
2841822	NM_145261.4(DNAJC19):c.210-2A>G	DNAJC19	Likely pathogenic	criteria provided, single submitter
2990462	NM_145261.4(DNAJC19):c.4-24_15del	DNAJC19	Likely pathogenic	criteria provided, single submitter
3064132	NM_145261.4(DNAJC19):c.281-2A>C	DNAJC19	Likely pathogenic	criteria provided, single submitter
993012	NM_145261.4(DNAJC19):c.158G>A (p.Gly53Glu)	DNAJC19	Likely pathogenic	no assertion criteria provided
1493559	NM_145261.4(DNAJC19):c.331G>C (p.Glu111Gln)	DNAJC19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214298	NM_145261.4(DNAJC19):c.181C>T (p.Arg61Trp)	DNAJC19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214299	NM_145261.4(DNAJC19):c.182G>A (p.Arg61Gln)	DNAJC19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
466328	NM_145261.4(DNAJC19):c.59G>A (p.Arg20His)	DNAJC19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
779507	NM_145261.4(DNAJC19):c.280+2dup	DNAJC19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1002196	NM_145261.4(DNAJC19):c.295A>G (p.Ile99Val)	DNAJC19	Uncertain significance	criteria provided, multiple submitters, no conflicts
1027288	NM_145261.4(DNAJC19):c.259C>T (p.Leu87Phe)	DNAJC19	Uncertain significance	criteria provided, single submitter
1035808	NM_145261.4(DNAJC19):c.344A>G (p.Lys115Arg)	DNAJC19	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
DNAJC19	Strong	Autosomal recessive	3-methylglutaconic aciduria type 5	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNAJC19	Orphanet:66634	Dilated cardiomyopathy with ataxia

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
DNAJC19	HGNC:30528	ENSG00000205981	Q96DA6	Mitochondrial import inner membrane translocase subunit TIM14	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DNAJC19	Mitochondrial import inner membrane translocase subunit TIM14	Mitochondrial co-chaperone which forms a complex with prohibitins to regulate cardiolipin remodeling.

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)
DNAJC19	Other/Unknown	no		DnaJ_domain, J_dom_sf

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
calcaneal tendon	1
tendon	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNAJC19	256	ubiquitous	marker	tendon of biceps brachii, tendon, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNAJC19	2,167

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNAJC19	Q96DA6	87.50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Mitochondrial protein import	1	167.9×	0.006	DNAJC19

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
regulation of cardiolipin metabolic process	1	8426.0×	8e-04	DNAJC19
genitalia development	1	1685.2×	0.002	DNAJC19
protein import into mitochondrial matrix	1	702.2×	0.003	DNAJC19
obsolete protein targeting to mitochondrion	1	581.1×	0.003	DNAJC19
protein folding	1	103.4×	0.014	DNAJC19
visual perception	1	79.5×	0.015	DNAJC19
intracellular protein transport	1	64.8×	0.015	DNAJC19

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DNAJC19	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	1	DNAJC19

Undrugged target profiles

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

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

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford