Combined oxidative phosphorylation defect type 23

Summary

Combined oxidative phosphorylation defect type 23 (MONDO:0014525) is a disease caused by GTPBP3 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GTPBP3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 42
• Phenotypes (HPO): 27

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		11	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0001639	Hypertrophic cardiomyopathy	Very frequent (80-99%)
HP:0003128	Lactic acidosis	Very frequent (80-99%)
HP:0000707	Abnormality of the nervous system	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0000505	Visual impairment	Occasional (5-29%)
HP:0000961	Cyanosis	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001635	Congestive heart failure	Occasional (5-29%)
HP:0001667	Right ventricular hypertrophy	Occasional (5-29%)
HP:0001712	Left ventricular hypertrophy	Occasional (5-29%)
HP:0001716	Wolff-Parkinson-White syndrome	Occasional (5-29%)
HP:0002415	Leukodystrophy	Occasional (5-29%)
HP:0002878	Respiratory failure	Occasional (5-29%)
HP:0003388	Easy fatigability	Occasional (5-29%)
HP:0008347	Decreased activity of mitochondrial complex IV	Occasional (5-29%)
HP:0008872	Feeding difficulties in infancy	Occasional (5-29%)
HP:0010307	Stridor	Occasional (5-29%)
HP:0011923	Decreased activity of mitochondrial complex I	Occasional (5-29%)
HP:0012666	Severely reduced ejection fraction	Occasional (5-29%)
HP:0012696	Abnormal thalamic MRI signal intensity	Occasional (5-29%)
HP:0012747	Abnormal brainstem MRI signal intensity	Occasional (5-29%)
HP:0012751	Abnormal basal ganglia MRI signal intensity	Occasional (5-29%)
HP:0012763	Paroxysmal dyspnea	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	combined oxidative phosphorylation defect type 23
Mondo ID	MONDO:0014525
OMIM	616198
Orphanet	444013
DOID	DOID:0111500
UMLS	C5567743
MedGen	1799166
GARD	0017759
Is cancer (heuristic)	no

Also known as: combined oxidative phosphorylation deficiency 23 · combined oxidative phosphorylation deficiency caused by mutation in GTPBP3 · combined oxidative phosphorylation deficiency type 23 · COXPD23 · GTPBP3 combined oxidative phosphorylation deficiency

Data availability: 42 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › combined oxidative phosphorylation deficiency › combined oxidative phosphorylation defect type 23

Related subtypes (57): severe X-linked mitochondrial encephalomyopathy, hepatoencephalopathy due to combined oxidative phosphorylation defect type 1, combined oxidative phosphorylation defect type 2, fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3, combined oxidative phosphorylation defect type 4, hypotonia with lactic acidemia and hyperammonemia, combined oxidative phosphorylation defect type 7, combined oxidative phosphorylation defect type 8, combined oxidative phosphorylation defect type 9, mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency, combined oxidative phosphorylation defect type 11, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, combined oxidative phosphorylation defect type 13, combined oxidative phosphorylation defect type 14, combined oxidative phosphorylation defect type 15, infantile hypertrophic cardiomyopathy due to MRPL44 deficiency, combined oxidative phosphorylation defect type 17, growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome, combined oxidative phosphorylation deficiency 19, combined oxidative phosphorylation defect type 20, combined oxidative phosphorylation defect type 21, mitochondrial proton-transporting ATP synthase complex deficiency, combined oxidative phosphorylation defect type 24, combined oxidative phosphorylation defect type 25, combined oxidative phosphorylation defect type 26, combined oxidative phosphorylation defect type 27, combined oxidative phosphorylation deficiency 28, combined oxidative phosphorylation deficiency 29, combined oxidative phosphorylation defect type 30, lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome, combined oxidative phosphorylation deficiency 40, combined oxidative phosphorylation deficiency 41, combined oxidative phosphorylation deficiency 42, combined oxidative phosphorylation deficiency 43, combined oxidative phosphorylation deficiency 44, combined oxidative phosphorylation deficiency 52, combined oxidative phosphorylation deficiency 53, combined oxidative phosphorylation deficiency 54, combined oxidative phosphorylation deficiency 37, combined oxidative phosphorylation deficiency 38, combined oxidative phosphorylation deficiency 39, combined oxidative phosphorylation deficiency 45, combined oxidative phosphorylation deficiency 46, combined oxidative phosphorylation deficiency 47, combined oxidative phosphorylation deficiency 48, combined oxidative phosphorylation deficiency 51, combined oxidative phosphorylation deficiency 32, combined oxidative phosphorylation deficiency 33, combined oxidative phosphorylation deficiency 34, combined oxidative phosphorylation deficiency 35, combined oxidative phosphorylation deficiency 36, combined oxidative phosphorylation deficiency 55, combined oxidative phosphorylation deficiency 56, combined oxidative phosphorylation deficiency 57, combined oxidative phosphorylation deficiency 58, combined oxidative phosphorylation deficiency 59, combined oxidative phosphorylation deficiency 60

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

42 retrieved; paginated sample, class counts are floors:

16 uncertain significance, 7 likely pathogenic, 6 pathogenic, 5 conflicting classifications of pathogenicity, 4 benign, 2 pathogenic/likely pathogenic, 1 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323041	NM_032620.4(GTPBP3):c.664+23_664+26del	GTPBP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1802991	NM_032620.4(GTPBP3):c.187C>T (p.Arg63Ter)	GTPBP3	Pathogenic	criteria provided, single submitter
180615	NM_032620.4(GTPBP3):c.1375G>A (p.Glu459Lys)	GTPBP3	Pathogenic	no assertion criteria provided
180616	NM_032620.4(GTPBP3):c.476A>T (p.Glu159Val)	GTPBP3	Pathogenic	no assertion criteria provided
180618	NM_032620.4(GTPBP3):c.1009G>C (p.Asp337His)	GTPBP3	Pathogenic	no assertion criteria provided
180619	NM_032620.4(GTPBP3):c.32_33delinsGTG (p.Gln11fs)	GTPBP3	Pathogenic	no assertion criteria provided
488527	NM_032620.4(GTPBP3):c.643G>T (p.Glu215Ter)	GTPBP3	Pathogenic	criteria provided, multiple submitters, no conflicts
642459	NM_032620.4(GTPBP3):c.865G>T (p.Glu289Ter)	GTPBP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1698817	NM_032620.4(GTPBP3):c.521G>C (p.Arg174Pro)	GTPBP3	Likely pathogenic	criteria provided, single submitter
180614	NM_032620.4(GTPBP3):c.1291dup (p.Arg431fs)	GTPBP3	Likely pathogenic	criteria provided, single submitter
2663971	NM_032620.4(GTPBP3):c.967del (p.Arg323fs)	GTPBP3	Likely pathogenic	criteria provided, single submitter
3336677	NM_032620.4(GTPBP3):c.846del (p.Thr283fs)	GTPBP3	Likely pathogenic	criteria provided, single submitter
3893164	NM_001195422.1(GTPBP3):c.104G>A (p.Trp35Ter)	GTPBP3	Likely pathogenic	criteria provided, single submitter
488526	NM_032620.4(GTPBP3):c.517C>T (p.Arg173Trp)	GTPBP3	Likely pathogenic	criteria provided, single submitter
488528	NM_032620.4(GTPBP3):c.1112T>C (p.Leu371Pro)	GTPBP3	Likely pathogenic	criteria provided, single submitter
1204496	NM_032620.4(GTPBP3):c.664+18T>G	GTPBP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1301803	NM_032620.4(GTPBP3):c.592-1G>C	GTPBP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1483843	NM_032620.4(GTPBP3):c.776A>G (p.Asn259Ser)	GTPBP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180617	NM_032620.4(GTPBP3):c.964G>C (p.Ala322Pro)	GTPBP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
488525	NM_032620.4(GTPBP3):c.440C>T (p.Ala147Val)	GTPBP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031119	NM_032620.4(GTPBP3):c.188G>A (p.Arg63Gln)	GTPBP3	Uncertain significance	criteria provided, single submitter
1031608	NM_032620.4(GTPBP3):c.1409G>A (p.Arg470Gln)	GTPBP3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1252038	NM_032620.4(GTPBP3):c.413C>A (p.Ala138Glu)	GTPBP3	Uncertain significance	no assertion criteria provided
1397558	NM_032620.4(GTPBP3):c.682G>T (p.Ala228Ser)	GTPBP3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1397700	NM_032620.4(GTPBP3):c.554G>A (p.Gly185Asp)	GTPBP3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1467442	NM_032620.4(GTPBP3):c.169G>C (p.Ala57Pro)	GTPBP3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1520589	NM_032620.4(GTPBP3):c.1424G>C (p.Gly475Ala)	GTPBP3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1699455	NM_032620.4(GTPBP3):c.1385G>A (p.Arg462Gln)	GTPBP3	Uncertain significance	criteria provided, single submitter
4078893	NM_032620.4(GTPBP3):c.1104CCT[2] (p.Leu371del)	GTPBP3	Uncertain significance	criteria provided, single submitter
4078894	NM_032620.4(GTPBP3):c.1387G>A (p.Val463Met)	GTPBP3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
GTPBP3	Definitive	Autosomal recessive	combined oxidative phosphorylation defect type 23	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GTPBP3	Orphanet:444013	Combined oxidative phosphorylation defect type 23

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
GTPBP3	HGNC:14880	ENSG00000130299	Q969Y2	5-taurinomethyluridine-[tRNA] synthase subunit GTPB3, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GTPBP3	5-taurinomethyluridine-[tRNA] synthase subunit GTPB3, mitochondrial	GTPase component of the GTPBP3-MTO1 complex that catalyzes the 5-taurinomethyluridine (taum(5)U) modification at the 34th wobble position (U34) of mitochondrial tRNAs (mt-tRNAs), which plays a role in mt-tRNA decoding and mitochondrial tra…

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)
GTPBP3	Other/Unknown	no		GTPase_MnmE, Small_GTP-bd, GTP-bd

Expression context

Cohort genes with no expression data: 0.

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
buccal mucosa cell	1
right adrenal gland	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GTPBP3	265	ubiquitous	yes	buccal mucosa cell, tendon of biceps brachii, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GTPBP3	2,135

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GTPBP3	Q969Y2	82.25

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
tRNA modification in the mitochondrion	1	1038.2×	1e-03	GTPBP3

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
mitochondrial tRNA wobble uridine modification	1	8426.0×	4e-04	GTPBP3
tRNA wobble uridine modification	1	1203.7×	0.001	GTPBP3
tRNA methylation	1	581.1×	0.002	GTPBP3

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
GTPBP3	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	GTPBP3

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)
GTPBP3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.