Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3

Summary

Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3 (MONDO:0012512) is a disease caused by TSFM (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TSFM (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 144

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

Identifiers

Disease identifiers

Field	Value
Canonical name	fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3
Mondo ID	MONDO:0012512
MeSH	C566467
OMIM	610505
Orphanet	168566
DOID	DOID:0111486
SNOMED CT	720951008
UMLS	C1864840
MedGen	355842
GARD	0017035
Is cancer (heuristic)	no

Also known as: combined oxidative phosphorylation deficiency 3 · combined oxidative phosphorylation deficiency caused by mutation in TSFM · combined oxidative phosphorylation deficiency type 3 · COXPD3 · fatal mitochondrial disease due to COXPD3 · TSFM combined oxidative phosphorylation deficiency

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 › fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3

Related subtypes (57): severe X-linked mitochondrial encephalomyopathy, hepatoencephalopathy due to combined oxidative phosphorylation defect type 1, combined oxidative phosphorylation defect type 2, 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 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

144 retrieved; paginated sample, class counts are floors:

47 uncertain significance, 35 likely pathogenic, 21 conflicting classifications of pathogenicity, 20 pathogenic/likely pathogenic, 10 likely benign, 6 benign, 4 benign/likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033357	NM_005726.6(TSFM):c.601C>T (p.Arg201Ter)	TSFM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070639	NM_005726.6(TSFM):c.85C>T (p.Gln29Ter)	TSFM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074148	NM_005726.6(TSFM):c.76C>T (p.Gln26Ter)	TSFM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076656	NM_005726.6(TSFM):c.403C>T (p.Gln135Ter)	TSFM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323719	NM_005726.6(TSFM):c.748G>T (p.Glu250Ter)	TSFM	Pathogenic	criteria provided, single submitter
1361252	NM_005726.6(TSFM):c.17C>A (p.Ser6Ter)	TSFM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1392216	NM_005726.6(TSFM):c.648T>G (p.Tyr216Ter)	TSFM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1395995	NM_005726.6(TSFM):c.571+1G>C	TSFM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451766	NM_005726.6(TSFM):c.27_28del (p.Phe10fs)	TSFM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
155718	NM_005726.6(TSFM):c.856C>T (p.Gln286Ter)	TSFM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1918350	NM_005726.6(TSFM):c.600dup (p.Arg201fs)	TSFM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2022300	NM_005726.6(TSFM):c.259C>T (p.Gln87Ter)	TSFM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2032839	NM_005726.6(TSFM):c.250A>T (p.Lys84Ter)	TSFM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2445917	NM_005726.6(TSFM):c.551del (p.Asp184fs)	TSFM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679363	NM_005726.6(TSFM):c.5C>A (p.Ser2Ter)	TSFM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2886331	NM_005726.6(TSFM):c.908_909insT (p.Gln303fs)	TSFM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3017558	NM_005726.6(TSFM):c.542C>A (p.Ser181Ter)	TSFM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5379	NM_005726.6(TSFM):c.934C>T (p.Arg312Trp)	TSFM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
845374	NM_005726.6(TSFM):c.557T>A (p.Leu186Ter)	TSFM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
854965	NM_005726.6(TSFM):c.399del (p.Lys133fs)	TSFM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
946171	NM_005726.6(TSFM):c.408_409del (p.Leu137fs)	TSFM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
424804	NM_001172696.1(TSFM):c.[355G>C];[997C>T]		Likely pathogenic	criteria provided, single submitter
1507022	NM_005726.6(TSFM):c.57+1G>A	TSFM	Likely pathogenic	criteria provided, multiple submitters, no conflicts
155719	NM_005726.6(TSFM):c.944G>A (p.Cys315Tyr)	TSFM	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1806099	NM_005726.6(TSFM):c.774G>C (p.Gln258His)	TSFM	Likely pathogenic	criteria provided, single submitter
242493	NM_001172696.1(TSFM):c.355G>C	TSFM	Likely pathogenic	criteria provided, single submitter
2503795	NM_005726.6(TSFM):c.192C>A (p.Cys64Ter)	TSFM	Likely pathogenic	criteria provided, single submitter
2679351	NM_005726.6(TSFM):c.797delinsGG (p.Leu266fs)	TSFM	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679352	NM_005726.6(TSFM):c.484-1G>A	TSFM	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679353	NM_005726.6(TSFM):c.808_809del (p.Ser270fs)	TSFM	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
TSFM	Strong	Autosomal recessive	fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TSFM	Orphanet:168566	Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3
AVIL	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome

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
TSFM	HGNC:12367	ENSG00000123297	P43897	Elongation factor Ts, mitochondrial	gencc,clinvar
AVIL	HGNC:14188	ENSG00000135407	O75366	Advillin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TSFM	Elongation factor Ts, mitochondrial	Associates with the EF-Tu.GDP complex and induces the exchange of GDP to GTP.
AVIL	Advillin	Ca(2+)-regulated actin-binding protein which plays an important role in actin bundling.

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)
TSFM	Other/Unknown	no		Transl_elong_EFTs/EF1B, UBA-like_sf, Transl_elong_EFTs/EF1B_dimer
AVIL	Other/Unknown	no		Villin_headpiece, Villin/Gelsolin, Gelsolin-like_dom

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
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1
cerebellar hemisphere	1
dorsal root ganglion	1
gastrocnemius	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TSFM	134	ubiquitous	marker	right adrenal gland, left adrenal gland, right adrenal gland cortex
AVIL	217	tissue_specific	marker	dorsal root ganglion, cerebellar hemisphere, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TSFM	3,286
AVIL	941

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TSFM	P43897	1
AVIL	O75366	1

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 translation elongation	1	126.9×	0.008	TSFM

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
regulation of diacylglycerol biosynthetic process	1	8426.0×	0.001	AVIL
mitochondrial translational elongation	1	2106.5×	0.002	TSFM
actin filament severing	1	601.9×	0.005	AVIL
barbed-end actin filament capping	1	401.2×	0.005	AVIL
actin polymerization or depolymerization	1	383.0×	0.005	AVIL
positive regulation of lamellipodium assembly	1	300.9×	0.006	AVIL
positive regulation of neuron projection development	1	68.5×	0.021	AVIL
actin filament organization	1	59.3×	0.021	AVIL
cilium assembly	1	36.8×	0.030	AVIL
nervous system development	1	23.0×	0.043	AVIL

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
TSFM	0	0
AVIL	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	TSFM, AVIL

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)
TSFM	0	—
AVIL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.