Combined oxidative phosphorylation defect type 7

disease

On this page

Also known as C12ORF65 combined oxidative phosphorylation deficiencycombined oxidative phosphorylation deficiency 7combined oxidative phosphorylation deficiency caused by mutation in C12ORF65combined oxidative phosphorylation deficiency type 7COXPD7severe C12ORF65-related combined oxidative phosphorylation defectsevere C12ORF65-related COXPD

Summary

Combined oxidative phosphorylation defect type 7 (MONDO:0013306) is a disease caused by MTRFR (GenCC Definitive), with 2 cohort genes.

At a glance

Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
Causal gene: MTRFR (GenCC Definitive)
Cohort genes: 2
ClinVar variants: 144
Phenotypes (HPO): 42

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

42 HPO clinical features (Orphanet curated; top 42 by frequency):

HPO ID	Term	Frequency
HP:0000505	Visual impairment	Very frequent (80-99%)
HP:0000648	Optic atrophy	Very frequent (80-99%)
HP:0003202	Skeletal muscle atrophy	Very frequent (80-99%)
HP:0000602	Ophthalmoplegia	Frequent (30-79%)
HP:0001123	Visual field defect	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002313	Spastic paraparesis	Frequent (30-79%)
HP:0002395	Lower limb hyperreflexia	Frequent (30-79%)
HP:0002936	Distal sensory impairment	Frequent (30-79%)
HP:0003477	Peripheral axonal neuropathy	Frequent (30-79%)
HP:0003693	Distal amyotrophy	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0007340	Lower limb muscle weakness	Frequent (30-79%)
HP:0031629	Impaired tandem gait	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001283	Bulbar palsy	Occasional (5-29%)
HP:0001284	Areflexia	Occasional (5-29%)
HP:0001349	Facial diplegia	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002376	Developmental regression	Occasional (5-29%)
HP:0002500	Abnormal cerebral white matter morphology	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0002590	Paralytic ileus	Occasional (5-29%)
HP:0002943	Thoracic scoliosis	Occasional (5-29%)
HP:0003380	Decreased number of peripheral myelinated nerve fibers	Occasional (5-29%)
HP:0003484	Upper limb muscle weakness	Occasional (5-29%)
HP:0005216	Impaired mastication	Occasional (5-29%)
HP:0007641	Dyschromatopsia	Occasional (5-29%)
HP:0008947	Floppy infant	Occasional (5-29%)
HP:0011471	Gastrostomy tube feeding in infancy	Occasional (5-29%)
HP:0012696	Abnormal thalamic MRI signal intensity	Occasional (5-29%)
HP:0012707	Elevated brain lactate level by MRS	Occasional (5-29%)
HP:0012747	Abnormal brainstem MRI signal intensity	Occasional (5-29%)
HP:0020049	Exodeviation	Occasional (5-29%)
HP:0200136	Oral-pharyngeal dysphagia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	combined oxidative phosphorylation defect type 7
Mondo ID	MONDO:0013306
OMIM	613559
Orphanet	254930
DOID	DOID:0111487
SNOMED CT	763204003
UMLS	C3150801
MedGen	462151
GARD	0017234
Is cancer (heuristic)	no

Also known as: C12ORF65 combined oxidative phosphorylation deficiency · C12orf65 combined oxidative phosphorylation deficiency · combined oxidative phosphorylation deficiency 7 · combined oxidative phosphorylation deficiency caused by mutation in C12ORF65 · combined oxidative phosphorylation deficiency caused by mutation in C12orf65 · combined oxidative phosphorylation deficiency type 7 · COXPD7 · severe C12ORF65-related combined oxidative phosphorylation defect · severe C12ORF65-related COXPD

Data availability: 144 ClinVar variants · 3 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 7

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

144 retrieved; paginated sample, class counts are floors:

77 uncertain significance, 34 likely benign, 14 pathogenic, 9 conflicting classifications of pathogenicity, 5 benign, 3 pathogenic/likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323989	NM_152269.5(MTRFR):c.43C>T (p.Arg15Ter)	MTRFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1681663	NM_152269.5(MTRFR):c.409A>T (p.Lys137Ter)	MTRFR	Pathogenic	criteria provided, single submitter
1878304	NM_152269.5(MTRFR):c.207_220del (p.Pro70fs)	MTRFR	Pathogenic	criteria provided, multiple submitters, no conflicts
214192	NM_152269.5(MTRFR):c.96_99dup (p.Pro34fs)	MTRFR	Pathogenic	criteria provided, multiple submitters, no conflicts
2427351	NC_000012.11:g.(?123741340)(123741578_?)del	MTRFR	Pathogenic	criteria provided, single submitter
2921346	NM_152269.5(MTRFR):c.193_194insCGAAAGCAGTTTG (p.Val65fs)	MTRFR	Pathogenic	criteria provided, single submitter
2952530	NM_152269.5(MTRFR):c.135_142dup (p.Asp48fs)	MTRFR	Pathogenic	criteria provided, single submitter
3244330	NC_000012.11:g.(?123738222)(123738523_?)del	MTRFR	Pathogenic	criteria provided, single submitter
3340697	NM_152269.5(MTRFR):c.259del (p.Ile87fs)	MTRFR	Pathogenic	criteria provided, multiple submitters, no conflicts
39582	NM_152269.5(MTRFR):c.394C>T (p.Arg132Ter)	MTRFR	Pathogenic	criteria provided, multiple submitters, no conflicts
53	NM_152269.5(MTRFR):c.248del (p.Val83fs)	MTRFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
54	NM_152269.5(MTRFR):c.210del (p.Gly72fs)	MTRFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
813299	GRCh37/hg19 12q24.31(chr12:123738222-123738503)	MTRFR	Pathogenic	criteria provided, single submitter
834522	NM_152269.5(MTRFR):c.307del (p.Gln103fs)	MTRFR	Pathogenic	criteria provided, single submitter
859045	NM_152269.5(MTRFR):c.33dup (p.Pro12fs)	MTRFR	Pathogenic	criteria provided, single submitter
91408	NM_152269.5(MTRFR):c.346del (p.Lys115_Val116insTer)	MTRFR	Pathogenic	criteria provided, single submitter
915979	GRCh37/hg19 12q24.31(chr12:123738221-123738503)	MTRFR	Pathogenic	no assertion criteria provided
1344257	NM_152269.5(MTRFR):c.333C>A (p.Ile111=)	MTRFR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
136595	NM_152269.5(MTRFR):c.243C>T (p.Cys81=)	MTRFR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
136596	NM_152269.5(MTRFR):c.413A>G (p.Lys138Arg)	MTRFR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307496	NM_152269.5(MTRFR):c.90G>A (p.Thr30=)	MTRFR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
493127	NM_152269.5(MTRFR):c.475T>C (p.Trp159Arg)	MTRFR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
697230	NM_152269.5(MTRFR):c.54G>A (p.Pro18=)	MTRFR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
697718	NM_152269.5(MTRFR):c.234C>A (p.Thr78=)	MTRFR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
747727	NM_152269.5(MTRFR):c.246G>A (p.Val82=)	MTRFR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
883442	NM_152269.5(MTRFR):c.336A>G (p.Leu112=)	MTRFR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
307492	NM_152269.4(MTRFR):c.-206G>T	MPHOSPH9	Uncertain significance	criteria provided, single submitter
307493	NM_152269.4(MTRFR):c.-128C>T	MPHOSPH9	Uncertain significance	criteria provided, single submitter
882665	NM_152269.4(MTRFR):c.-166T>C	MPHOSPH9	Uncertain significance	criteria provided, single submitter
882666	NM_152269.4(MTRFR):c.-132A>G	MPHOSPH9	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
MTRFR	Definitive	Autosomal recessive	combined oxidative phosphorylation defect type 7	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MTRFR	Orphanet:254930	Combined oxidative phosphorylation defect type 7
MTRFR	Orphanet:320375	Autosomal recessive spastic paraplegia type 55

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MTRFR	HGNC:26784	ENSG00000130921	Q9H3J6	Mitochondrial translation release factor in rescue	gencc,clinvar
MPHOSPH9	HGNC:7215	ENSG00000051825	Q99550	M-phase phosphoprotein 9	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MTRFR	Mitochondrial translation release factor in rescue	Part of a mitoribosome-associated quality control pathway that prevents aberrant translation by responding to interruptions during elongation.
MPHOSPH9	M-phase phosphoprotein 9	Negatively regulates cilia formation by recruiting the CP110-CEP97 complex (a negative regulator of ciliogenesis) at the distal end of the mother centriole in ciliary cells.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MTRFR	Other/Unknown	no		Pep_chain_release_fac_I, Pep_chain_release_fac_I_sf, Mito_Transl_Release_Factor
MPHOSPH9	Other/Unknown	no		MPHOSPH9

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
pancreatic ductal cell	1
thymus	1
adrenal tissue	1
primordial germ cell in gonad	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MTRFR	250	ubiquitous	marker	thymus, oocyte, pancreatic ductal cell
MPHOSPH9	244	ubiquitous	marker	ventricular zone, adrenal tissue, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MPHOSPH9	3,068
MTRFR	2,061

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MTRFR	Q9H3J6	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MPHOSPH9	Q99550	55.83

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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 ribosome-associated quality control	1	122.8×	0.008	MTRFR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial translational termination	1	1685.2×	0.002	MTRFR
negative regulation of cilium assembly	1	401.2×	0.004	MPHOSPH9
rescue of stalled cytosolic ribosome	1	240.7×	0.004	MTRFR

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
MTRFR	0	0
MPHOSPH9	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	MTRFR, MPHOSPH9

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MTRFR	0	—
MPHOSPH9	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: MTRFR, MPHOSPH9