MTO1

Summary

MTO1 (mitochondrial tRNA translation optimization 1, HGNC:19261) is a protein-coding gene on chromosome 6q13, encoding 5-taurinomethyluridine-[tRNA] synthase subunit MTO1, mitochondrial (Q9Y2Z2). 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 translation.

This gene encodes a mitochondrial protein thought to be involved in mitochondrial tRNA modification. The encoded protein may also play a role in the expression of the non-syndromic and aminoglycoside-induced deafness phenotypes associated with a specific mutation in the mitochondrial 12S rRNA gene. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 25821 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 842 total — 54 pathogenic, 17 likely-pathogenic
• Phenotypes (HPO): 28
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_012123

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19261
Approved symbol	MTO1
Name	mitochondrial tRNA translation optimization 1
Location	6q13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000135297
Ensembl biotype	protein_coding
OMIM	614667
Entrez	25821

Gene structure

Transcript identifiers

Ensembl transcripts: 82 — 54 nonsense_mediated_decay, 16 retained_intron, 11 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000370300, ENST00000370305, ENST00000370308, ENST00000415228, ENST00000415954, ENST00000442897, ENST00000445187, ENST00000462039, ENST00000466977, ENST00000485082, ENST00000487960, ENST00000498286, ENST00000518210, ENST00000521032, ENST00000521156, ENST00000522205, ENST00000523763, ENST00000524046, ENST00000679352, ENST00000679364, ENST00000679411, ENST00000679418, ENST00000679524, ENST00000679591, ENST00000679592, ENST00000679604, ENST00000679612, ENST00000679627, ENST00000679675, ENST00000679730, ENST00000679763, ENST00000679808, ENST00000679870, ENST00000679900, ENST00000679905, ENST00000679947, ENST00000679993, ENST00000680034, ENST00000680131, ENST00000680195, ENST00000680238, ENST00000680266, ENST00000680289, ENST00000680350, ENST00000680405, ENST00000680428, ENST00000680544, ENST00000680563, ENST00000680570, ENST00000680601, ENST00000680609, ENST00000680686, ENST00000680758, ENST00000680775, ENST00000680794, ENST00000680841, ENST00000680875, ENST00000680902, ENST00000681094, ENST00000681141, ENST00000681165, ENST00000681204, ENST00000681212, ENST00000681254, ENST00000681267, ENST00000681284, ENST00000681294, ENST00000681337, ENST00000681438, ENST00000681500, ENST00000681509, ENST00000681579, ENST00000681610, ENST00000681620, ENST00000681624, ENST00000681691, ENST00000681705, ENST00000681890, ENST00000681932, ENST00000861273, ENST00000969378, ENST00000969379

RefSeq mRNA: 3 — MANE Select: NM_012123 NM_001123226, NM_012123, NM_133645

CCDS: CCDS34485, CCDS47452, CCDS4979

Canonical transcript exons

ENST00000498286 — 12 exons

Exon	Start	End
ENSE00000000080	73461737	73462071
ENSE00001845913	73500574	73509236
ENSE00003459292	73479936	73480126
ENSE00003460662	73482040	73482244
ENSE00003519723	73466489	73466606
ENSE00003524080	73466209	73466408
ENSE00003571911	73480675	73480805
ENSE00003572797	73479732	73479844
ENSE00003610915	73497736	73497896
ENSE00003622293	73482449	73482620
ENSE00003627072	73492234	73492352
ENSE00003660011	73473365	73473654

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 91.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.3392 / max 151.6203, expressed in 1811 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
68577	11.3774	1774
68578	6.6464	1725
68581	1.1881	291
68579	0.9388	566
68580	0.1680	79
68582	0.0205	3

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	91.79	gold quality
sperm	CL:0000019	91.76	gold quality
endothelial cell	CL:0000115	91.07	gold quality
granulocyte	CL:0000094	91.01	gold quality
right lobe of liver	UBERON:0001114	90.75	gold quality
epithelium of nasopharynx	UBERON:0001951	90.32	gold quality
calcaneal tendon	UBERON:0003701	90.15	gold quality
male germ cell	CL:0000015	90.03	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.81	gold quality
liver	UBERON:0002107	89.67	gold quality
nephron tubule	UBERON:0001231	89.34	gold quality
heart right ventricle	UBERON:0002080	89.24	gold quality
tibia	UBERON:0000979	89.04	gold quality
biceps brachii	UBERON:0001507	88.63	gold quality
parietal pleura	UBERON:0002400	88.53	gold quality
gingival epithelium	UBERON:0001949	88.44	gold quality
spleen	UBERON:0002106	88.25	gold quality
tendon	UBERON:0000043	88.20	gold quality
muscle of leg	UBERON:0001383	88.12	gold quality
gastrocnemius	UBERON:0001388	88.12	gold quality
pleura	UBERON:0000977	88.05	gold quality
visceral pleura	UBERON:0002401	87.85	gold quality
jejunal mucosa	UBERON:0000399	87.77	gold quality
leukocyte	CL:0000738	87.68	gold quality
lymph node	UBERON:0000029	87.66	gold quality
superficial temporal artery	UBERON:0001614	87.66	gold quality
right ovary	UBERON:0002118	87.66	gold quality
ventricular zone	UBERON:0003053	87.62	gold quality
metanephric glomerulus	UBERON:0004736	87.59	gold quality
muscle organ	UBERON:0001630	87.54	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.40

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1

miRNA regulators (miRDB)

47 targeting MTO1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-2116-3P	99.74	64.32	889
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-4470	99.66	69.35	1767
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-802	99.61	67.70	1254
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-4328	99.57	71.06	4094

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 20)

• identification of full-length cDNA and elucidation of genomic organization of the human MTO1 homolog (PMID:12011058)
• Phenotype of non-syndromic deafness associated with the mitochondrial A1555G mutation is modulated by mitochondrial RNA modifying enzymes MTO1 and GTPBP3. (PMID:15542390)
• proposed linkage in chromosome 8 and the association with TRMU and MTO1 genes were studied in A1555G deafness (PMID:18391568)
• MTO1 mutations have roles in hypertrophic cardiomyopathy and lactic acidosis (PMID:22608499)
• MTO1 mutations are commonly associated with a presentation of hypertrophic cardiomyopathy, lactic acidosis, and MRC deficiency. (PMID:23929671)
• Nuclear-encoded mitochondrial MTO1 and MRPL41 are regulated in an opposite epigenetic mode based on estrogen receptor status in breast cancer. (PMID:24160266)
• Results show that post-transcriptional expression of GTPBP3, MTO1 and TRMU genes is down-regulated, leading to mt-tRNA hypomodification and contributing to mitochondrial dysfunction in MELAS cybrids. (PMID:25149473)
• MTO1 mediates tRNA modification and controls mitochondrial translation rate in a highly tissue-specific manner associated with tissue-specific oxidative phosphorylation defects. (PMID:25552653)
• Optic neuropathy, cardiomyopathy, and cognitive disability was found in patients with a homozygous mutation in the nuclear MTO1 and a mitochondrial MT-TF variant. (PMID:26061759)
• Whole-exome sequencing (WES) indicated a double homozygous mutation in the mitochondrial tRNA translation optimization 1 protein (MTO1) gene (p.R504C and p.V557M) in two of the patients and the homozygous mutation p.R504C in the other. (PMID:27256614)
• Low MTO1 expression is associated with Mitochondrial diseases in neoplasms. (PMID:28740091)
• MTO1 deficiency is lethal in some but not all cases, and a genotype-phenotype relation is suggested. Aside from lactic acidosis and cardiomyopathy, developmental delay and other phenotypic features affecting multiple organ systems are often present in these patients, suggesting a broader spectrum than hitherto reported. (PMID:29331171)
• Defects in the mitochondrial tRNA modification enzymes MTO1 and GTPBP3 promote different metabolic reprogramming through a HIF-PPARgamma-UCP2-AMPK axis. (PMID:29348686)
• Two novel variants (c.[253G > A];[938G > A]) in the MTO1 gene were identified in a child with cardiomyopathy with early-onset brain disease. (PMID:29440775)
• CircMTO1 inhibits liver fibrosis via regulation of miR-17-5p and Smad7. (PMID:31148365)
• Novel Mitochondrial Translation Optimizer-1 Mutations as a Cause of Hereditary Optic Neuropathy. (PMID:31842146)
• Circular RNA MTO1 Inhibits the Proliferation and Invasion of Ovarian Cancer Cells Through the miR-182-5p/KLF15 Axis. (PMID:32731816)
• CircMTO1 inhibits ox-LDL-stimulated vascular smooth muscle cell proliferation and migration via regulating the miR-182-5p/RASA1 axis. (PMID:34238206)
• CircMTO1 suppresses hepatocellular carcinoma progression via the miR-541-5p/ZIC1 axis by regulating Wnt/beta-catenin signaling pathway and epithelial-to-mesenchymal transition. (PMID:34930906)
• Clinical and genetic analysis of combined oxidative phosphorylation defificiency-10 caused by MTO1 mutation. (PMID:34990597)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mto1	ENSDARG00000055679
mus_musculus	Mto1	ENSMUSG00000032342
rattus_norvegicus	Mto1	ENSRNOG00000037659
drosophila_melanogaster	CG4610	FBGN0034735
caenorhabditis_elegans		WBGENE00009944

Protein

Protein identifiers

5-taurinomethyluridine-[tRNA] synthase subunit MTO1, mitochondrial — Q9Y2Z2 (reviewed: Q9Y2Z2)

Alternative names: Mitochondrial tRNA translation optimization 1, Protein MTO1 homolog, mitochondrial

All UniProt accessions (32): A0A7P0T851, A0A7P0T8X3, A0A7P0T8Y9, A0A7P0T930, A0A7P0T957, A0A7P0T9I0, A0A7P0T9M4, A0A7P0T9M7, A0A7P0T9Q8, A0A7P0T9S8, A0A7P0TA02, A0A7P0TA27, A0A7P0TAK2, A0A7P0TAU1, Q9Y2Z2, A0A7P0TB43, A0A7P0TB86, A0A7P0TB93, A0A7P0TBB2, A0A7P0TBB3, A0A7P0TBC1, A0A7P0Z443, A0A7P0Z471, A0A7P0Z482, A0A7P0Z4B1, A0A7P0Z4D4, A0A7P0Z4R0, E5RFF7, E7EWI1, E9PHR8, H0YB81, H0YBI9

UniProt curated annotations — full annotation on UniProt →

Function. 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 translation. Taum(5)U formation on mammalian mt-tRNA requires the presence of both GTPBP3-mediated GTPase activity and MTO1 catalytic activity.

Subunit / interactions. Homodimer; forms a dimer in the presence of potassium. Interacts with GTPBP3; forms the GTPBP3-MTO1 complex composed of homodimers of GTPBP3 and MTO1.

Subcellular location. Mitochondrion.

Tissue specificity. Ubiquitously expressed in various tissues, but with a markedly elevated expression in tissues of high metabolic rates including cochlea.

Disease relevance. Combined oxidative phosphorylation deficiency 10 (COXPD10) [MIM:614702] An autosomal recessive disorder resulting in variable defects of mitochondrial oxidative respiration. Affected individuals present in infancy with hypertrophic cardiomyopathy and lactic acidosis. The severity is variable, but can be fatal in the most severe cases. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the MnmG family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q9Y2Z2-1	3, 4	yes
Q9Y2Z2-2	1
Q9Y2Z2-3	2
Q9Y2Z2-4	5
Q9Y2Z2-5	6
Q9Y2Z2-6	7

RefSeq proteins (3): NP_001116698, NP_036255, NP_598400 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002218	MnmG-rel	Family
IPR020595	MnmG-rel_CS	Conserved_site
IPR026904	MnmG_C	Domain
IPR036188	FAD/NAD-bd_sf	Homologous_superfamily
IPR040131	MnmG_N	Domain
IPR044920	MnmG_C_subdom_sf	Homologous_superfamily
IPR047001	MnmG_C_subdom	Domain
IPR049312	GIDA_C_N	Domain

Pfam: PF01134, PF13932, PF21680

Catalyzed reactions (Rhea), 1 shown:

• 5,10-methylenetetrahydrofolate + uridine(34) in tRNA + taurine + GTP + A + H2O = 5-taurinomethyluridine(34) in tRNA + 7,8-dihydrofolate + GDP + AH2 + phosphate + H(+) (RHEA:83279)

UniProt features (16 total): splice variant 6, binding site 4, sequence conflict 2, transit peptide 1, chain 1, sequence variant 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2Z2-F1	85.95	0.65

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 43–48; 155; 218; 432

Post-translational modifications (1): 533

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6787450	tRNA modification in the mitochondrion
R-HSA-72306	tRNA processing
R-HSA-8953854	Metabolism of RNA

MSigDB gene sets: 184 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_TRNA_METABOLIC_PROCESS, GOBP_RNA_METHYLATION, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, GOBP_RNA_MODIFICATION, GOBP_MITOCHONDRIAL_RNA_PROCESSING, GOBP_TRNA_METHYLATION, GOBP_MITOCHONDRIAL_RNA_METABOLIC_PROCESS, GOBP_TRNA_THREONYLCARBAMOYLADENOSINE_METABOLIC_PROCESS, GOBP_METHYLATION, ALCALA_APOPTOSIS, GOBP_TRNA_PROCESSING, REACTOME_METABOLISM_OF_RNA, GOBP_TRNA_MODIFICATION, GOCC_TRANSFERASE_COMPLEX

GO Biological Process (4): tRNA methylation (GO:0030488), mitochondrial tRNA wobble uridine modification (GO:0070899), tRNA wobble uridine modification (GO:0002098), tRNA processing (GO:0008033)

GO Molecular Function (3): RNA binding (GO:0003723), flavin adenine dinucleotide binding (GO:0050660), tRNA 5-taurinomethyluridine synthase activity (GO:0160236)

GO Cellular Component (5): mitochondrion (GO:0005739), cytosol (GO:0005829), transferase complex (GO:1990234), GTPBP3-MTO1 complex (GO:7770010), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
tRNA processing	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
cellular anatomical structure	2
RNA methylation	1
tRNA modification	1
tRNA wobble uridine modification	1
mitochondrion	1
mitochondrial tRNA modification	1
tRNA wobble base modification	1
RNA processing	1
tRNA metabolic process	1
nucleic acid binding	1
nucleotide binding	1
anion binding	1
transferase activity	1
catalytic activity, acting on a tRNA	1
intracellular membrane-bounded organelle	1
catalytic complex	1
transferase complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2130 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MTO1	TRMU	O75648	969
MTO1	GTPBP3	Q969Y2	932
MTO1	TRAF4	Q9BUZ4	786
MTO1	VCF1	Q969W3	744
MTO1	PUS1	Q9Y606	722
MTO1	CCDC127	Q96BQ5	718
MTO1	TUBGCP3	Q96CW5	696
MTO1	TRIT1	Q9H3H1	678
MTO1	MTFMT	Q96DP5	666
MTO1	ELAC2	Q9BQ52	640
MTO1	CNOT10	Q9H9A5	616
MTO1	FASTKD3	Q14CZ7	602
MTO1	TADA2B	Q86TJ2	597
MTO1	SUPT7L	O94864	594
MTO1	NSUN3	Q9H649	590

IntAct

77 interactions, top by confidence:

A	B	Type	Score
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
DNAJC7	PLD2	psi-mi:“MI:0914”(association)	0.640
TSC22D4	TSC22D2	psi-mi:“MI:0914”(association)	0.640
BPNT1	GTPBP10	psi-mi:“MI:0914”(association)	0.530
IL13RA2	METTL15	psi-mi:“MI:0914”(association)	0.530
CAPN2	MYO9A	psi-mi:“MI:0914”(association)	0.530
CCNJL	PIK3C2A	psi-mi:“MI:0914”(association)	0.530
YBEY	NME4	psi-mi:“MI:0914”(association)	0.530
LRP1	NME4	psi-mi:“MI:0914”(association)	0.530
IARS2	GAK	psi-mi:“MI:0914”(association)	0.530
SDF4	GTPBP6	psi-mi:“MI:0914”(association)	0.530
ELP2	DNAJA2	psi-mi:“MI:0914”(association)	0.530
RBP4	POLR3D	psi-mi:“MI:0914”(association)	0.530
HAX1	CHEK1	psi-mi:“MI:0914”(association)	0.530
MTO1	SUV39H1	psi-mi:“MI:0915”(physical association)	0.370
MTO1	KDM1A	psi-mi:“MI:0915”(physical association)	0.370
FASTKD3	VWA8	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
PRKCB	HNRNPDL	psi-mi:“MI:0914”(association)	0.350
PRKCB	CHEK1	psi-mi:“MI:0914”(association)	0.350
FKBP5	IFT56	psi-mi:“MI:0914”(association)	0.350
ABTB2	IFT56	psi-mi:“MI:0914”(association)	0.350
LURAP1	CIBAR1	psi-mi:“MI:0914”(association)	0.350
BBS7	TARS3	psi-mi:“MI:0914”(association)	0.350
NXF2B	MEIOC	psi-mi:“MI:0914”(association)	0.350
TENT5A	TMEM131L	psi-mi:“MI:0914”(association)	0.350
MALSU1	VWA8	psi-mi:“MI:0914”(association)	0.350
DNAJA2	DENND11	psi-mi:“MI:0914”(association)	0.350
LY6G5B	POTEF	psi-mi:“MI:0914”(association)	0.350

BioGRID (102): MTO1 (Affinity Capture-MS), MTO1 (Affinity Capture-MS), MTO1 (Affinity Capture-MS), MTO1 (Affinity Capture-MS), MTO1 (Affinity Capture-MS), MTO1 (Affinity Capture-MS), MTO1 (Affinity Capture-MS), MTO1 (Affinity Capture-MS), MTO1 (Affinity Capture-MS), MTO1 (Affinity Capture-MS), MTO1 (Affinity Capture-MS), MTO1 (Affinity Capture-MS), MTO1 (Affinity Capture-MS), MTO1 (Affinity Capture-MS), MTO1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D8PC43, A0A1D8PLH0, A0A1U8QNG8, A3KPF2, D0EAP4, F4I1L3, F4JCU3, F8QQQ7, G9BIY1, I1S130, J9VU26, O02734, O13963, O23461, O23722, P04385, P13045, P17423, P24521, P32377, P49915, P53602, P54868, Q02155, Q04409, Q09580, Q0P570, Q10313, Q38970, Q38A34, Q3THK7, Q4V7C6, Q4WNV9, Q4WV38, Q54YQ9, Q5RA96, Q5U403, Q62967, Q69R21, Q6BY07

Diamond homologs: A1UQU7, A3PNS6, A4WVY9, A4YJT4, A5CDS8, A5E8G8, A5II62, A5VT19, A6UEE8, A6WX77, A7HSL1, A7ZTV2, A8EXC3, A8F0G3, A8GLZ9, A8GQL7, A8GUR1, A8I266, A8LPC3, A9IZX9, A9M9E4, B0BW03, B0CJG1, B0T6E1, B0UJI8, B1LL68, B1M186, B1X9W9, B1ZGG2, B2IJQ4, B3CLI3, B3CR62, B3Q8A7, B5YXE5, B6JAJ1, B7L889, B7M597, B7N2I0, B7NR43, B7UMK6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

842 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	54
Likely pathogenic	17
Uncertain significance	367
Likely benign	323
Benign	38

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069917	NM_012123.4(MTO1):c.1692del (p.Val565fs)	Pathogenic
1073223	NM_012123.4(MTO1):c.667C>T (p.Gln223Ter)	Pathogenic
1076245	NM_012123.4(MTO1):c.1498C>T (p.Arg500Ter)	Pathogenic
1384098	NM_012123.4(MTO1):c.1750dup (p.Ile584fs)	Pathogenic
1404043	NM_012123.4(MTO1):c.961A>T (p.Lys321Ter)	Pathogenic
1420202	NM_012123.4(MTO1):c.1789C>T (p.Gln597Ter)	Pathogenic
1432815	NM_012123.4(MTO1):c.1848T>G (p.Tyr616Ter)	Pathogenic
1453242	NM_012123.4(MTO1):c.429_444del (p.Asn144fs)	Pathogenic
1455779	NM_012123.4(MTO1):c.967_968del (p.Leu323fs)	Pathogenic
1456323	NC_000006.11:g.(?74171578)(74171814_?)del	Pathogenic
1460431	NC_000006.11:g.(?74171578)(74192363_?)del	Pathogenic
1979871	NM_012123.4(MTO1):c.1136del (p.Gly379fs)	Pathogenic
1986427	NM_012123.4(MTO1):c.970del (p.Arg324fs)	Pathogenic
2016252	NM_012123.4(MTO1):c.724del (p.Arg242fs)	Pathogenic
2119738	NM_012123.4(MTO1):c.413del (p.Met138fs)	Pathogenic
2129741	NM_012123.4(MTO1):c.525_526del (p.Val176fs)	Pathogenic
2150102	NM_012123.4(MTO1):c.1421dup (p.Leu474fs)	Pathogenic
2150945	NM_012123.4(MTO1):c.1495C>T (p.Gln499Ter)	Pathogenic
2157351	NM_012123.4(MTO1):c.1643dup (p.Asp549fs)	Pathogenic
2196399	NM_012123.4(MTO1):c.1451G>A (p.Arg484Gln)	Pathogenic
2231281	NM_012123.4(MTO1):c.939-2A>G	Pathogenic
2425760	NC_000006.11:g.(?74183068)(74183397_?)del	Pathogenic
2425763	NC_000006.11:g.(?74175912)(74183397_?)del	Pathogenic
2425764	NC_000006.11:g.(?74189435)(74192363_?)del	Pathogenic
2691508	NM_012123.4(MTO1):c.1274del (p.Gly425fs)	Pathogenic
2718305	NM_012123.4(MTO1):c.137dup (p.His46fs)	Pathogenic
2832033	NM_012123.4(MTO1):c.648del (p.Gln216fs)	Pathogenic
2858104	NM_012123.4(MTO1):c.239_242del (p.Ser80fs)	Pathogenic
2863233	NM_012123.4(MTO1):c.1533_1536del (p.Glu512fs)	Pathogenic
2901473	NM_012123.4(MTO1):c.937C>T (p.Arg313Ter)	Pathogenic

SpliceAI

2116 predictions. Top by Δscore:

Variant	Effect	Δscore
6:73466483:TGACA:T	acceptor_loss	1.0000
6:73466484:GACA:G	acceptor_loss	1.0000
6:73466485:ACAG:A	acceptor_loss	1.0000
6:73466487:A:AG	acceptor_gain	1.0000
6:73466487:AG:A	acceptor_loss	1.0000
6:73466488:G:GG	acceptor_gain	1.0000
6:73466488:GA:G	acceptor_gain	1.0000
6:73466488:GAA:G	acceptor_gain	1.0000
6:73466488:GAAA:G	acceptor_gain	1.0000
6:73466605:GG:G	donor_gain	1.0000
6:73466606:GG:G	donor_gain	1.0000
6:73466606:GGTA:G	donor_loss	1.0000
6:73466607:G:GG	donor_gain	1.0000
6:73466607:GTA:G	donor_loss	1.0000
6:73466608:TAC:T	donor_loss	1.0000
6:73479730:A:AG	acceptor_gain	1.0000
6:73479731:G:GG	acceptor_gain	1.0000
6:73480668:T:A	acceptor_gain	1.0000
6:73480669:G:A	acceptor_gain	1.0000
6:73480671:TCA:T	acceptor_loss	1.0000
6:73480673:A:AG	acceptor_gain	1.0000
6:73480673:A:C	acceptor_loss	1.0000
6:73480674:G:GG	acceptor_gain	1.0000
6:73480674:GGCT:G	acceptor_gain	1.0000
6:73480791:G:GT	donor_gain	1.0000
6:73480803:CAAGT:C	donor_loss	1.0000
6:73480804:AAGT:A	donor_loss	1.0000
6:73480805:AGT:A	donor_loss	1.0000
6:73480806:G:GA	donor_loss	1.0000
6:73480806:G:GG	donor_gain	1.0000

AlphaMissense

4479 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:73461996:G:T	G48W	0.999
6:73466225:T:A	N78K	0.998
6:73466225:T:G	N78K	0.998
6:73480789:A:T	E440V	0.998
6:73461976:T:A	V41D	0.997
6:73462005:G:C	A51P	0.997
6:73480801:C:A	A444D	0.997
6:73461994:C:A	A47D	0.996
6:73462045:T:C	L64P	0.996
6:73466221:G:A	C77Y	0.996
6:73466236:G:A	G82D	0.996
6:73466274:G:C	A95P	0.996
6:73466369:A:C	R126S	0.996
6:73466369:A:T	R126S	0.996
6:73473409:G:T	G194W	0.996
6:73473415:T:C	F196L	0.996
6:73473417:T:A	F196L	0.996
6:73473417:T:G	F196L	0.996
6:73479940:T:C	C315R	0.996
6:73482040:G:C	G446R	0.996
6:73482041:G:A	G446D	0.996
6:73482140:T:C	L479P	0.996
6:73461992:T:A	H46Q	0.995
6:73461992:T:G	H46Q	0.995
6:73461997:G:A	G48E	0.995
6:73462024:G:C	R57P	0.995
6:73466220:T:C	C77R	0.995
6:73466222:T:G	C77W	0.995
6:73466353:C:A	A121D	0.995
6:73466361:G:C	G124R	0.995

dbSNP variants (sampled 300 via entrez): RS1000042060 (6:73492705 A>G), RS1000054872 (6:73462839 A>G), RS1000072139 (6:73507077 G>T), RS1000079909 (6:73479735 G>A), RS1000264113 (6:73475271 G>GT), RS1000318809 (6:73507448 A>C), RS1000337299 (6:73475093 T>G), RS1000432861 (6:73482172 A>C,G), RS1000456066 (6:73487250 T>C), RS1000480966 (6:73470263 A>G), RS1000493500 (6:73481567 A>G), RS1000507886 (6:73488088 G>A), RS1000508383 (6:73486928 G>C), RS1000623929 (6:73487816 C>T), RS1000734296 (6:73494541 A>G)

Disease associations

OMIM: gene MIM:614667 | disease phenotypes: MIM:614702

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (3): mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency (MONDO:0013865), mitochondrial oxidative phosphorylation disorder (MONDO:0016387), hereditary motor neuron disease (MONDO:0024257)

Orphanet (3): Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency (Orphanet:314637), Mitochondrial oxidative phosphorylation disorder (Orphanet:223713), Genetic motor neuron disease (Orphanet:98505)

HPO phenotypes

28 total (28 of 28 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000648	Optic atrophy
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001332	Dystonia
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0001541	Ascites
HP:0001562	Oligohydramnios
HP:0001639	Hypertrophic cardiomyopathy
HP:0001640	Cardiomegaly
HP:0001662	Bradycardia
HP:0001698	Pericardial effusion
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0001987	Hyperammonemia
HP:0002151	Increased circulating lactate concentration
HP:0002202	Pleural effusion
HP:0002465	Poor speech
HP:0003128	Lactic acidosis
HP:0003348	Hyperalaninemia
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0011924	Decreased activity of mitochondrial complex III
HP:0011968	Feeding difficulties

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

30 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	2
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
beta-lapachone	decreases expression, increases expression	1
sodium arsenite	increases abundance, increases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
ICG 001	increases expression	1
abrine	increases expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Air Pollutants, Occupational	affects expression	1
Arsenic	increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Hydrogen Peroxide	affects cotreatment, decreases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1
Testosterone	increases expression	1
Theophylline	affects cotreatment, decreases expression	1
Tretinoin	decreases expression	1
Isotretinoin	decreases expression	1
Sodium Selenite	increases expression	1
Antirheumatic Agents	increases expression	1
Acrylamide	increases expression	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D9KR	Ubigene HEK293 MTO1 KO	Transformed cell line	Female
CVCL_E2CX	HAP1 MTO1 (-) 2	Cancer cell line	Male
CVCL_XQ77	HAP1 MTO1 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.