Combined oxidative phosphorylation deficiency 35

Summary

Combined oxidative phosphorylation deficiency 35 (MONDO:0054742) is a disease caused by TRIT1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: TRIT1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 34

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	combined oxidative phosphorylation deficiency 35
Mondo ID	MONDO:0054742
OMIM	617873
DOID	DOID:0111464
UMLS	C4693466
MedGen	1639653
GARD	0025966
Is cancer (heuristic)	no

Also known as: combined oxidative phosphorylation deficiency 35 · COXPD35

Data availability: 34 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 deficiency 35

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 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 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

34 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
1300160	NM_017646.6(TRIT1):c.568C>T (p.Gln190Ter)	TRIT1	Pathogenic	criteria provided, single submitter
1686274	NM_017646.6(TRIT1):c.967C>T (p.Arg323Trp)	TRIT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1700786	NM_017646.6(TRIT1):c.1029del (p.Val344fs)	TRIT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2692355	NM_017646.6(TRIT1):c.1171_1172del (p.Lys391fs)	TRIT1	Pathogenic	no assertion criteria provided
2692358	NM_017646.6(TRIT1):c.882del (p.Glu295fs)	TRIT1	Pathogenic	no assertion criteria provided
417684	NM_017646.6(TRIT1):c.22C>T (p.Arg8Ter)	TRIT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
432133	NM_017646.6(TRIT1):c.979C>T (p.Arg327Ter)	TRIT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
492943	NM_017646.6(TRIT1):c.968G>A (p.Arg323Gln)	TRIT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
545453	NM_017646.6(TRIT1):c.334del (p.Arg112fs)	TRIT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1201174	NM_017646.6(TRIT1):c.1225G>A (p.Glu409Lys)	TRIT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2585517	NM_017646.6(TRIT1):c.1235-2A>G	TRIT1	Likely pathogenic	criteria provided, single submitter
3341369	NM_017646.6(TRIT1):c.1085_1086del (p.Pro362fs)	TRIT1	Likely pathogenic	criteria provided, single submitter
1029628	NM_017646.6(TRIT1):c.289G>A (p.Asp97Asn)	TRIT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
417681	NM_017646.6(TRIT1):c.848T>G (p.Ile283Ser)	TRIT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
417682	NM_017646.6(TRIT1):c.1204C>T (p.Arg402Ter)	TRIT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
545454	NM_017646.6(TRIT1):c.326T>C (p.Ile109Thr)	TRIT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1365813	NM_017646.6(TRIT1):c.16G>A (p.Ala6Thr)	MYCL-AS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3238842	NM_017646.6(TRIT1):c.65C>T (p.Thr22Ile)	MYCL-AS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3377737	NM_017646.6(TRIT1):c.23G>C (p.Arg8Pro)	MYCL-AS1	Uncertain significance	criteria provided, single submitter
4277830	NM_017646.6(TRIT1):c.98G>A (p.Gly33Asp)	MYCL-AS1	Uncertain significance	criteria provided, single submitter
1033850	NM_017646.6(TRIT1):c.1214T>C (p.Ile405Thr)	TRIT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1679848	NM_017646.6(TRIT1):c.1034A>G (p.Tyr345Cys)	TRIT1	Uncertain significance	criteria provided, single submitter
1683955	NM_017646.6(TRIT1):c.847A>G (p.Ile283Val)	TRIT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1687363	NM_017646.6(TRIT1):c.415-4A>G	TRIT1	Uncertain significance	criteria provided, single submitter
2437334	NM_017646.6(TRIT1):c.1232C>T (p.Ala411Val)	TRIT1	Uncertain significance	criteria provided, single submitter
2627613	NM_017646.6(TRIT1):c.865C>T (p.His289Tyr)	TRIT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3341368	NM_017646.6(TRIT1):c.528G>T (p.Lys176Asn)	TRIT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3731391	NM_017646.6(TRIT1):c.887G>A (p.Gly296Glu)	TRIT1	Uncertain significance	criteria provided, single submitter
4072426	NM_017646.6(TRIT1):c.323A>T (p.Asp108Val)	TRIT1	Uncertain significance	criteria provided, single submitter
417680	NM_017646.6(TRIT1):c.1256A>C (p.His419Pro)	TRIT1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 0 · 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
TRIT1	Strong	Autosomal recessive	combined oxidative phosphorylation deficiency 35	3

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TRIT1	HGNC:20286	ENSG00000043514	Q9H3H1	tRNA dimethylallyltransferase	gencc,clinvar
MYCL-AS1	HGNC:40386	ENSG00000236546		MYCL antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRIT1	tRNA dimethylallyltransferase	Catalyzes the transfer of a dimethylallyl group onto the adenine at position 37 of both cytosolic and mitochondrial tRNAs, leading to the formation of N6-(dimethylallyl)adenosine (i6A37).

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRIT1	Transcription factor	no	2.5.1.75	Matrin/U1-like-C_Znf_C2H2, IPT, P-loop_NTPase
MYCL-AS1	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
oocyte	1
skin of leg	1
ganglionic eminence	1
left ovary	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRIT1	283	ubiquitous	marker	oocyte, body of pancreas, skin of leg
MYCL-AS1	99	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, ganglionic eminence, left ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRIT1	2,890
MYCL-AS1	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TRIT1	Q9H3H1	85.08

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
tRNA modification in the mitochondrion	1	1038.2×	0.004	TRIT1
tRNA processing	1	356.9×	0.005	TRIT1
tRNA modification in the nucleus and cytosol	1	292.8×	0.005	TRIT1
Metabolism of RNA	1	41.7×	0.024	TRIT1

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 modification	1	3370.4×	6e-04	TRIT1
tRNA modification	1	601.9×	0.002	TRIT1

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
TRIT1	0	0
MYCL-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TRIT1	2.5.1.75	tRNA dimethylallyltransferase

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	2	TRIT1, MYCL-AS1

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)
TRIT1	0	—
MYCL-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.