Combined oxidative phosphorylation defect type 15

Summary

Combined oxidative phosphorylation defect type 15 (MONDO:0013987) is a disease caused by MTFMT (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MTFMT (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 28

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		16	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	combined oxidative phosphorylation defect type 15
Mondo ID	MONDO:0013987
OMIM	614947
Orphanet	319524
DOID	DOID:0111491
SNOMED CT	763203009
UMLS	C4706313
MedGen	1646555
GARD	0017456
Is cancer (heuristic)	no

Also known as: combined oxidative phosphorylation defect type 15 · combined oxidative phosphorylation deficiency 15 · combined oxidative phosphorylation deficiency caused by mutation in MTFMT · combined oxidative phosphorylation deficiency type 15 · COXPD15 · MTFMT combined oxidative phosphorylation deficiency

Data availability: 28 ClinVar variants · 4 GenCC gene-disease records.

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 15

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, 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 23, 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

28 retrieved; paginated sample, class counts are floors:

7 pathogenic, 6 uncertain significance, 6 likely pathogenic, 4 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
120309	NM_139242.4(MTFMT):c.452C>T (p.Pro151Leu)	MTFMT	Pathogenic	no assertion criteria provided
133323	NM_139242.4(MTFMT):c.146_153del (p.Arg49fs)	MTFMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
133324	NM_139242.4(MTFMT):c.878G>A (p.Ser293Asn)	MTFMT	Pathogenic	no assertion criteria provided
133325	NM_139242.4(MTFMT):c.73C>T (p.Gln25Ter)	MTFMT	Pathogenic	criteria provided, single submitter
39827	NM_139242.4(MTFMT):c.626C>T (p.Ser209Leu)	MTFMT	Pathogenic	criteria provided, multiple submitters, no conflicts
39828	NM_139242.4(MTFMT):c.382C>T (p.Arg128Ter)	MTFMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39829	NM_139242.4(MTFMT):c.374C>T (p.Ser125Leu)	MTFMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39830	NM_139242.4(MTFMT):c.994C>T (p.Arg332Ter)	MTFMT	Pathogenic	criteria provided, multiple submitters, no conflicts
435899	NM_139242.4(MTFMT):c.219_222del (p.Glu74fs)	MTFMT	Pathogenic	criteria provided, multiple submitters, no conflicts
488549	NM_139242.4(MTFMT):c.91C>T (p.Arg31Ter)	MTFMT	Pathogenic	criteria provided, single submitter
1334390	NM_139242.4(MTFMT):c.459G>A (p.Trp153Ter)	MTFMT	Likely pathogenic	criteria provided, single submitter
216965	NM_139242.4(MTFMT):c.1116del (p.Pro373fs)	MTFMT	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2429485	NM_139242.4(MTFMT):c.722-2A>G	MTFMT	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4277422	NM_139242.4(MTFMT):c.419+1G>C	MTFMT	Likely pathogenic	criteria provided, single submitter
4277423	NM_139242.4(MTFMT):c.310C>T (p.Gln104Ter)	MTFMT	Likely pathogenic	criteria provided, single submitter
4849459	NM_139242.4(MTFMT):c.209+2_209+14del	MTFMT	Likely pathogenic	criteria provided, single submitter
1027737	NM_139242.4(MTFMT):c.419+3A>G	MTFMT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031157	NM_139242.4(MTFMT):c.34C>A (p.Pro12Thr)	MTFMT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2083783	NM_139242.4(MTFMT):c.645+3A>G	MTFMT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
985377	NM_139242.4(MTFMT):c.1129A>C (p.Lys377Gln)	MTFMT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1027738	NM_139242.4(MTFMT):c.460C>T (p.Arg154Cys)	MTFMT	Uncertain significance	criteria provided, single submitter
1027739	NM_139242.4(MTFMT):c.466C>T (p.Pro156Ser)	MTFMT	Uncertain significance	criteria provided, single submitter
1031156	NM_139242.4(MTFMT):c.1123AAG[2] (p.Lys377del)	MTFMT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1492324	NM_139242.4(MTFMT):c.1063C>G (p.Gln355Glu)	MTFMT	Uncertain significance	criteria provided, multiple submitters, no conflicts
3068458	NM_139242.4(MTFMT):c.368T>C (p.Val123Ala)	MTFMT	Uncertain significance	criteria provided, single submitter
548003	NM_139242.4(MTFMT):c.19C>G (p.Arg7Gly)	MTFMT	Uncertain significance	criteria provided, multiple submitters, no conflicts
138264	NM_139242.4(MTFMT):c.796C>T (p.Arg266Cys)	MTFMT	Benign	criteria provided, multiple submitters, no conflicts
440931	NM_139242.4(MTFMT):c.172T>A (p.Phe58Ile)	MTFMT	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
MTFMT	Definitive	Autosomal recessive	combined oxidative phosphorylation defect type 15	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MTFMT	Orphanet:319524	Combined oxidative phosphorylation defect type 15

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
MTFMT	HGNC:29666	ENSG00000103707	Q96DP5	Methionyl-tRNA formyltransferase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MTFMT	Methionyl-tRNA formyltransferase, mitochondrial	Methionyl-tRNA formyltransferase that formylates methionyl-tRNA in mitochondria and is crucial for translation initiation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MTFMT	Enzyme (other)	yes	2.1.2.9	Formyl_transf_N, Formyl_trans_C, Fmt

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
buccal mucosa cell	1
cardiac muscle of right atrium	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MTFMT	245	ubiquitous	marker	left ventricle myocardium, buccal mucosa cell, cardiac muscle of right atrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTFMT	2,143

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MTFMT	Q96DP5	86.08

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 translation initiation	1	126.9×	0.008	MTFMT

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
conversion of methionyl-tRNA to N-formyl-methionyl-tRNA	1	16852.0×	6e-05	MTFMT

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
MTFMT	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MTFMT	2.1.2.9	methionyl-tRNA formyltransferase

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	1	MTFMT
E	Difficult family or no structure, no drug	0

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)
MTFMT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.