TRMU

Summary

TRMU (tRNA mitochondrial 2-thiouridylase, HGNC:25481) is a protein-coding gene on chromosome 22q13.31, encoding Mitochondrial tRNA-specific 2-thiouridylase 1 (O75648). Catalyzes the 2-thiolation of uridine at the wobble position (U34) of mitochondrial tRNA(Lys), tRNA(Glu) and tRNA(Gln).

This nuclear gene encodes a mitochondrial tRNA-modifying enzyme. The encoded protein catalyzes the 2-thiolation of uridine on the wobble positions of tRNA(Lys), tRNA(Glu), and tRNA(Gln), resulting in the formation of 5-taurinomethyl-2-thiouridine moieties. Mutations in this gene may cause transient infantile liver failure. Polymorphisms in this gene may also influence the severity of deafness caused by mitochondrial 12S ribosomal RNA mutations. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 55687 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 874 total — 51 pathogenic, 92 likely-pathogenic
• Phenotypes (HPO): 51
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_018006

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25481
Approved symbol	TRMU
Name	tRNA mitochondrial 2-thiouridylase
Location	22q13.31
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10140, MTO2, MTU1
Ensembl gene	ENSG00000100416
Ensembl biotype	protein_coding
OMIM	610230
Entrez	55687

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 13 protein_coding, 7 nonsense_mediated_decay, 7 retained_intron, 5 protein_coding_CDS_not_defined

ENST00000381019, ENST00000381021, ENST00000441818, ENST00000453630, ENST00000456595, ENST00000457572, ENST00000463785, ENST00000465378, ENST00000470831, ENST00000476901, ENST00000479648, ENST00000485175, ENST00000485559, ENST00000486620, ENST00000491612, ENST00000493556, ENST00000496831, ENST00000642562, ENST00000642923, ENST00000643137, ENST00000644006, ENST00000645026, ENST00000645190, ENST00000647301, ENST00000867893, ENST00000867894, ENST00000867895, ENST00000867896, ENST00000923368, ENST00000923369, ENST00000963412, ENST00000963413

RefSeq mRNA: 5 — MANE Select: NM_018006 NM_001282782, NM_001282783, NM_001282784, NM_001282785, NM_018006

CCDS: CCDS14075, CCDS63510

Canonical transcript exons

ENST00000645190 — 11 exons

Exon	Start	End
ENSE00001868921	46356842	46357340
ENSE00003491544	46353767	46353867
ENSE00003495244	46352264	46352330
ENSE00003511236	46343262	46343368
ENSE00003574042	46346422	46346544
ENSE00003619503	46337779	46337944
ENSE00003641331	46355444	46355588
ENSE00003662686	46350291	46350463
ENSE00003690147	46352121	46352174
ENSE00003690835	46355990	46356072
ENSE00003829336	46335714	46335846

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 95.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.8765 / max 291.2097, expressed in 1821 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
192810	22.4309	1821
192811	0.4456	204

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	95.39	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.46	gold quality
metanephros cortex	UBERON:0010533	94.43	gold quality
lower esophagus mucosa	UBERON:0035834	94.13	gold quality
cerebellar hemisphere	UBERON:0002245	93.88	gold quality
cerebellar cortex	UBERON:0002129	93.74	gold quality
right uterine tube	UBERON:0001302	93.64	gold quality
adenohypophysis	UBERON:0002196	93.64	gold quality
right atrium auricular region	UBERON:0006631	93.32	gold quality
right lobe of thyroid gland	UBERON:0001119	93.19	gold quality
body of pancreas	UBERON:0001150	93.13	gold quality
ventricular zone	UBERON:0003053	93.07	gold quality
left ovary	UBERON:0002119	92.93	gold quality
right ovary	UBERON:0002118	92.89	gold quality
left lobe of thyroid gland	UBERON:0001120	92.71	gold quality
skin of leg	UBERON:0001511	92.59	gold quality
granulocyte	CL:0000094	92.51	gold quality
heart left ventricle	UBERON:0002084	92.47	gold quality
pituitary gland	UBERON:0000007	92.43	gold quality
tibial nerve	UBERON:0001323	92.43	gold quality
skin of abdomen	UBERON:0001416	92.28	gold quality
endocervix	UBERON:0000458	92.27	gold quality
body of uterus	UBERON:0009853	92.19	gold quality
body of stomach	UBERON:0001161	92.12	gold quality
mucosa of transverse colon	UBERON:0004991	92.05	gold quality
cardiac ventricle	UBERON:0002082	91.99	gold quality
right frontal lobe	UBERON:0002810	91.89	gold quality
ectocervix	UBERON:0012249	91.89	gold quality
minor salivary gland	UBERON:0001830	91.88	gold quality
cerebellum	UBERON:0002037	91.86	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

6 targeting TRMU, 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-33A-3P	99.70	70.27	3362
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-6858-3P	96.37	64.41	771
HSA-MIR-1237-5P	95.38	62.21	451
HSA-MIR-4488	95.38	62.00	443
HSA-MIR-4697-5P	95.38	61.72	457

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 17)

• Identification and characterization of a mouse gene encoding one component of the enzyme complex responsible for the nucleotide modification at wobble position of mitochondrial tRNA anticodons. (PMID:14746906)
• identification and characterization of a tRNA-modifying enzyme MTU1 (mitochondrial tRNA-specific 2-thiouridylase 1) that is responsible for the 2-thiolation of the wobble position in human and yeast mt tRNAs (PMID:15509579)
• MTO2 may act as a modifier gene, modulating the phenotypic expression of the deafness-associated A1491G or C1409T mutation in mitochondrial 12 S rRNA (PMID:15944150)
• These observations suggest that human TRMU may modulate the phenotypic manifestation of the deafness-associated mitochondrial 12S rRNA mutations. (PMID:16513084)
• The mutated TRMU, related to transfer RNA modification, acting as a modifier factor modulates the phenotypic manifestation of deafness-associated 12S rRNA mutations. (PMID:16826519)
• TRMU G28T single nucleotide polymorphism is present in 1 of the studied families for neurosensory nonsyndromic deafness (PMID:18391568)
• There is a window of time whereby patients with TRMU mutations are at increased risk of developing liver failure. (PMID:19732863)
• MTU1 is not required for mitochondrial translation. (PMID:21890497)
• An additional, heterozygous mutation was detected in TRMU/MTU1. Although subject myoblasts and myotubes contained half the normal levels of TRMU, thiolation of mitochondrial tRNAs was normal. (PMID:22504945)
• 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)
• The A10S mutation caused marked decreases in 2-thiouridine modification of U34 of tRNA(Lys), tRNA(Glu) and tRNA(Gln) However, the A10S mutation mildly increased the aminoacylated efficiency of tRNAs (PMID:28049726)
• Heteroplasmic transition of A to G at position 1555 of MT-RNR1 gene was identified in all affected individuals co-existing with nuclear c.28G>T (p.A10S) variant in the TRMU gene, only in some patients with hereditary non-syndromic hearing loss of variable severity. (PMID:30205178)
• Mtu1 defects are correlated with reduced osteogenic differentiation. (PMID:33431792)
• TRMU deficiency: A broad clinical spectrum responsive to cysteine supplementation. (PMID:33485800)
• Genetic correction of TRMU allele restored the mitochondrial dysfunction-induced deficiencies in iPSCs-derived hair cells of hearing-impaired patients. (PMID:35467742)
• Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants. (PMID:36305855)
• Pathological mutations promote proteolysis of mitochondrial tRNA-specific 2-thiouridylase 1 (MTU1) via mitochondrial caseinolytic peptidase (CLPP). (PMID:38113276)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	trmu	ENSDARG00000043734
mus_musculus	Trmu	ENSMUSG00000022386
rattus_norvegicus	Trmu	ENSRNOG00000016465
drosophila_melanogaster	CG3021	FBGN0040337
caenorhabditis_elegans		WBGENE00007114

Protein

Protein identifiers

Mitochondrial tRNA-specific 2-thiouridylase 1 — O75648 (reviewed: O75648)

Alternative names: MTO2 homolog

All UniProt accessions (7): O75648, A0A2R8Y4R7, A0A2R8Y6L6, A0A2R8YDK3, A0A2R8YFQ3, B4DZN5, Q2PPL5

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the 2-thiolation of uridine at the wobble position (U34) of mitochondrial tRNA(Lys), tRNA(Glu) and tRNA(Gln). Required for the formation of 5-taurinomethyl-2-thiouridine (tm5s2U) of mitochondrial tRNA(Lys), tRNA(Glu), and tRNA(Gln) at the wobble position. ATP is required to activate the C2 atom of the wobble base.

Subcellular location. Mitochondrion.

Tissue specificity. Ubiquitous. Abundantly expressed in tissues with high metabolic rates including heart, liver, kidney, and brain.

Disease relevance. Deafness, aminoglycoside-induced (DFNI) [MIM:580000] A form of sensorineural deafness characterized by moderate-to-profound hearing loss and mitochondrial inheritance. It is induced by exposure to aminoglycosides. The gene represented in this entry acts as a disease modifier. DFNI is caused by mutations in mitochondrial rRNA genes, including homoplasmic A1555G and C1494T mutations in the highly conserved decoding site of the mitochondrial 12S rRNA. Mutated TRMU modulates the phenotypic manifestation of these mutations. Liver failure, infantile, transient (LFIT) [MIM:613070] A transient disorder of hepatic function characterized by elevated liver enzymes, jaundice, vomiting, coagulopathy, hyperbilirubinemia, increased serum lactate. Patients who survive the initial acute episode can recover, show normal development and have no recurrence. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. During the reaction, ATP is used to activate the C2 atom of U34 by adenylation. After this, the persulfide sulfur on the catalytic cysteine is transferred to the C2 atom of the wobble base (U34) of mitochondrial tRNA(Lys), tRNA(Glu) and tRNA(Gln). The reaction probably involves hydrogen sulfide that is generated from the persulfide intermediate and that acts as a nucleophile towards the activated C2 atom on U34. Subsequently, a transient disulfide bond is formed between the two active site cysteine residues.

Similarity. Belongs to the MnmA/TRMU family.

Isoforms (5)

UniProt ID	Names	Canonical?
O75648-1	1	yes
O75648-2	2
O75648-3	3
O75648-4	4
O75648-5	5

RefSeq proteins (5): NP_001269711, NP_001269712, NP_001269713, NP_001269714, NP_060476* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004506	MnmA-like	Family
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR023382	MnmA-like_central_sf	Homologous_superfamily
IPR046884	MnmA-like_central	Domain
IPR046885	MnmA-like_C	Domain

Pfam: PF03054, PF20258, PF20259

Enzyme classification (BRENDA):

• EC 2.1.1.61 — tRNA 5-(aminomethyl)-2-thiouridylate-methyltransferase (BRENDA: 3 organisms, 6 substrates, 4 inhibitors, 0 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
TRNA CONTAINING 5-AMINOMETHYL-2-THIOURIDINE	—	0

Catalyzed reactions (Rhea), 1 shown:

• 5-taurinomethyluridine(34) in tRNA + S-sulfanyl-L-cysteinyl-[protein] + AH2 + ATP = 5-taurinomethyl-2-thiouridine(34) in tRNA + L-cysteinyl-[protein] + A + AMP + diphosphate + H(+) (RHEA:47040)

UniProt features (30 total): sequence variant 8, splice variant 5, region of interest 4, site 3, binding site 3, sequence conflict 2, active site 2, chain 1, disulfide bond 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75648-F1	89.60	0.78

Functional residue map

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

Catalytic / active sites (5): 127 (interaction with trna); 267 (interaction with trna); 367 (interaction with trna); 101 (nucleophile); 222 (cysteine persulfide intermediate)

Ligand- & substrate-binding residues (3): 10–17; 36; 126

Disulfide bonds (1): 101–222

Mutagenesis-validated functional residues (1):

Position	Phenotype
16	loss of activity.

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: 208 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, GOBP_TRNA_METABOLIC_PROCESS, GOBP_RNA_MODIFICATION, CCAGGTT_MIR490, CAGCCTC_MIR4855P, GOBP_TRNA_PROCESSING, REACTOME_METABOLISM_OF_RNA, GOBP_TRNA_MODIFICATION, GINESTIER_BREAST_CANCER_ZNF217_AMPLIFIED_DN, chr22q13, CAGCTTT_MIR320, KIM_WT1_TARGETS_DN, GOMF_TRNA_BINDING

GO Biological Process (3): tRNA wobble position uridine thiolation (GO:0002143), tRNA processing (GO:0008033), methylation (GO:0032259)

GO Molecular Function (9): tRNA binding (GO:0000049), ATP binding (GO:0005524), tRNA-5-taurinomethyluridine 2-sulfurtransferase activity (GO:0061708), nucleotide binding (GO:0000166), RNA binding (GO:0003723), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740), sulfurtransferase activity (GO:0016783)

GO Cellular Component (1): mitochondrion (GO:0005739)

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
tRNA wobble uridine modification	1
tRNA thio-modification	1
RNA processing	1
tRNA metabolic process	1
metabolic process	1
RNA binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
sulfurtransferase activity	1
catalytic activity, acting on a tRNA	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid binding	1
binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
transferase activity, transferring sulphur-containing groups	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1612 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRMU	MTO1	Q9Y2Z2	969
TRMU	GTPBP3	Q969Y2	858
TRMU	PUS1	Q9Y606	718
TRMU	TRIT1	Q9H3H1	712
TRMU	NFS1	Q9Y697	665
TRMU	CTU1	Q7Z7A3	647
TRMU	MTFMT	Q96DP5	646
TRMU	TRMT5	Q32P41	635
TRMU	TUFM	P49411	625
TRMU	AFP	P02771	610
TRMU	CTU2	Q2VPK5	608
TRMU	DGUOK	P78532	604
TRMU	TSFM	P43897	578
TRMU	MOCS3	O95396	576
TRMU	TFB1M	Q8WVM0	549

IntAct

27 interactions, top by confidence:

A	B	Type	Score
HSPD1	NUDT19	psi-mi:“MI:0914”(association)	0.710
MTA3	KDM1A	psi-mi:“MI:0914”(association)	0.530
YBEY	NME4	psi-mi:“MI:0914”(association)	0.530
MBL2	TRMU	psi-mi:“MI:0915”(physical association)	0.500
MBL2	TRMU	psi-mi:“MI:0914”(association)	0.500
ZNF185	TRMU	psi-mi:“MI:0915”(physical association)	0.400
IL1R2	QSOX1	psi-mi:“MI:0914”(association)	0.350
SMOC1	TCAF2	psi-mi:“MI:0914”(association)	0.350
CARTPT	MEIS1	psi-mi:“MI:0914”(association)	0.350
RAP2A	CHEK1	psi-mi:“MI:0914”(association)	0.350
GPSM3	PHF1	psi-mi:“MI:0914”(association)	0.350
FAM219B	SPAG9	psi-mi:“MI:0914”(association)	0.350
HOXC10	TRMU	psi-mi:“MI:0914”(association)	0.350
THUMPD3	TRMU	psi-mi:“MI:0914”(association)	0.350
COQ4	TRMU	psi-mi:“MI:0914”(association)	0.350
TRMU	HSPD1	psi-mi:“MI:0914”(association)	0.350
TRMU	IFT56	psi-mi:“MI:0914”(association)	0.350
FECH	GTPBP10	psi-mi:“MI:0914”(association)	0.350
CCNL2	ANKRD17	psi-mi:“MI:0914”(association)	0.350
EEF1A2	TRMU	psi-mi:“MI:0914”(association)	0.350
FTL		psi-mi:“MI:0914”(association)	0.350
LRRC46	GTPBP6	psi-mi:“MI:0914”(association)	0.350
MFSD14A	FAM171A2	psi-mi:“MI:0914”(association)	0.350
TRMU	b4079	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (100): TRMU (Affinity Capture-MS), TRMU (Affinity Capture-MS), TRMU (Affinity Capture-MS), TRMU (Affinity Capture-MS), TRMU (Affinity Capture-MS), TRMU (Affinity Capture-MS), TRMU (Affinity Capture-MS), TRMU (Affinity Capture-MS), TRMU (Negative Genetic), TRMU (Affinity Capture-MS), FAT3 (Affinity Capture-MS), TRMU (Affinity Capture-MS), TRMU (Affinity Capture-MS), STIP1 (Affinity Capture-MS), HSPD1 (Affinity Capture-MS)

ESM2 similar proteins: A4FV98, A6NKP2, A6QLY2, O18735, O43488, O75382, O75648, O77485, O77486, O88676, P04626, P23764, P25325, P34059, P52848, Q02353, Q0VD18, Q10836, Q10981, Q10982, Q28113, Q32KH5, Q32KJ6, Q3U129, Q3UHN9, Q4R766, Q571E4, Q5I0D5, Q5RB73, Q5RJL2, Q6AYT7, Q6P988, Q7RTV5, Q7Z4H8, Q8CIW5, Q8K093, Q8N2K0, Q8WNQ7, Q96AZ1, Q96SL4

Diamond homologs: A0AIW1, A0RJ05, A3CRB2, A4IR87, A4VYE7, A4W4N7, A4W9E5, A5ITE6, A5UFX6, A6QHG3, A6T7K3, A6U290, A7GT74, A7MFV2, A7X333, A7Z745, A7ZKS3, A7ZZ88, A8FFP0, A8MEV9, A8YUQ2, A8Z4F9, A9N4K8, B1HUL3, B1I833, B1IUD4, B1LI10, B1WC37, B1XA43, B2IRK2, B2TZ86, B4EVG2, B5E605, B5XSN3, B8DDZ8, B8ZK04, B9IYG1, C1CAE7, C1CBU0, C1CI29

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	51
Likely pathogenic	92
Uncertain significance	178
Likely benign	399
Benign	53

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073932	NM_018006.5(TRMU):c.290_327dup (p.Phe110delinsLeuThrTer)	Pathogenic
1076499	NM_018006.5(TRMU):c.706-1G>A	Pathogenic
1293	NM_018006.5(TRMU):c.815G>A (p.Gly272Asp)	Pathogenic
1294	NM_018006.5(TRMU):c.2T>A (p.Met1Lys)	Pathogenic
1373404	NM_018006.5(TRMU):c.597del (p.Phe199fs)	Pathogenic
1392569	NM_018006.5(TRMU):c.749dup (p.Asn250fs)	Pathogenic
1394772	NM_018006.5(TRMU):c.943G>T (p.Glu315Ter)	Pathogenic
1451272	NM_018006.5(TRMU):c.732dup (p.Ile245fs)	Pathogenic
1451436	NM_018006.5(TRMU):c.706-1G>C	Pathogenic
1454736	NM_018006.5(TRMU):c.418dup (p.Glu140fs)	Pathogenic
1963294	NM_018006.5(TRMU):c.914_941dup (p.Glu316fs)	Pathogenic
1967642	NM_018006.5(TRMU):c.162_163del (p.Cys54_Glu55delinsTer)	Pathogenic
2006296	NM_018006.5(TRMU):c.809_810del (p.Ile270fs)	Pathogenic
2036251	NM_018006.5(TRMU):c.409G>T (p.Glu137Ter)	Pathogenic
2057735	NM_018006.5(TRMU):c.584dup (p.Leu195fs)	Pathogenic
2113146	NM_018006.5(TRMU):c.1045del (p.Asp349fs)	Pathogenic
2118337	NM_018006.5(TRMU):c.954_957dup (p.Ala320fs)	Pathogenic
2123687	NM_018006.5(TRMU):c.882dup (p.Thr295fs)	Pathogenic
2126798	NM_018006.5(TRMU):c.184C>T (p.Gln62Ter)	Pathogenic
2130216	NM_018006.5(TRMU):c.541_542dup (p.Gln182fs)	Pathogenic
2138457	NM_018006.5(TRMU):c.1041_1044del (p.Asn347fs)	Pathogenic
215287	NM_018006.5(TRMU):c.718C>T (p.Arg240Ter)	Pathogenic
2762980	NM_018006.5(TRMU):c.574_575dup (p.Gly193fs)	Pathogenic
2773143	NM_018006.5(TRMU):c.27C>A (p.Cys9Ter)	Pathogenic
2811643	NM_018006.5(TRMU):c.417dup (p.Glu140Ter)	Pathogenic
2821546	NM_018006.5(TRMU):c.906_907del (p.Asp303fs)	Pathogenic
2826057	NM_018006.5(TRMU):c.695del (p.Phe232fs)	Pathogenic
2839286	NM_018006.5(TRMU):c.712C>T (p.Gln238Ter)	Pathogenic
2840455	NM_018006.5(TRMU):c.648_649AG[1] (p.Ser218fs)	Pathogenic
2844881	NM_018006.5(TRMU):c.936dup (p.Ile313fs)	Pathogenic

SpliceAI

2387 predictions. Top by Δscore:

Variant	Effect	Δscore
22:46346409:A:AG	acceptor_gain	1.0000
22:46346410:A:G	acceptor_gain	1.0000
22:46346417:CACA:C	acceptor_loss	1.0000
22:46346419:CAG:C	acceptor_loss	1.0000
22:46346420:A:G	acceptor_loss	1.0000
22:46346545:G:GA	donor_loss	1.0000
22:46346546:TAA:T	donor_loss	1.0000
22:46352170:TTCAG:T	donor_loss	1.0000
22:46352172:CAGGT:C	donor_loss	1.0000
22:46352173:AG:A	donor_loss	1.0000
22:46352174:GGTG:G	donor_loss	1.0000
22:46352175:G:GA	donor_loss	1.0000
22:46352176:T:A	donor_loss	1.0000
22:46353765:AGGTT:A	acceptor_gain	1.0000
22:46353766:GGTTG:G	acceptor_gain	1.0000
22:46355581:GGCAC:G	donor_gain	1.0000
22:46355582:GCAC:G	donor_gain	1.0000
22:46355584:ACTAG:A	donor_loss	1.0000
22:46355585:C:CG	donor_gain	1.0000
22:46355586:TAGGT:T	donor_loss	1.0000
22:46355988:A:AG	acceptor_gain	1.0000
22:46355989:G:GG	acceptor_gain	1.0000
22:46356840:A:AG	acceptor_gain	1.0000
22:46356841:G:GG	acceptor_gain	1.0000
22:46337770:C:CA	acceptor_gain	0.9900
22:46337775:GCAG:G	acceptor_loss	0.9900
22:46337776:CA:C	acceptor_loss	0.9900
22:46337777:A:AG	acceptor_gain	0.9900
22:46337777:A:AT	acceptor_loss	0.9900
22:46337778:G:GC	acceptor_loss	0.9900

AlphaMissense

2790 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:46346437:C:A	A124D	0.997
22:46350344:A:C	S178R	0.996
22:46350346:C:A	S178R	0.996
22:46350346:C:G	S178R	0.996
22:46355504:T:A	W312R	0.996
22:46355504:T:C	W312R	0.996
22:46356871:C:G	C377W	0.996
22:46335813:A:C	S17R	0.994
22:46335815:C:A	S17R	0.994
22:46335815:C:G	S17R	0.994
22:46337879:C:G	C61W	0.994
22:46343331:A:C	K106N	0.994
22:46343331:A:T	K106N	0.994
22:46343332:T:C	F107L	0.994
22:46343334:T:A	F107L	0.994
22:46343334:T:G	F107L	0.994
22:46355997:T:G	C342W	0.994
22:46356869:T:C	C377R	0.994
22:46337793:G:T	G33W	0.993
22:46343354:C:A	A114D	0.993
22:46356876:G:A	G379D	0.993
22:46356878:A:C	S380R	0.993
22:46356880:C:A	S380R	0.993
22:46356880:C:G	S380R	0.993
22:46346436:G:C	A124P	0.992
22:46350423:C:A	A204D	0.992
22:46356875:G:C	G379R	0.992
22:46337794:G:A	G33E	0.991
22:46337878:G:A	C61Y	0.991
22:46350402:A:T	K197I	0.991

dbSNP variants (sampled 300 via entrez): RS1000009336 (22:46345054 T>C), RS1000043779 (22:46341441 G>T), RS1000082419 (22:46345298 C>G,T), RS1000103863 (22:46351902 C>A,T), RS1000190683 (22:46349488 A>G,T), RS1000231492 (22:46334542 G>C,T), RS1000261352 (22:46340094 A>G), RS1000374679 (22:46353654 A>C), RS1000412182 (22:46351734 A>G), RS1000524267 (22:46338510 A>T), RS1000667278 (22:46349680 T>C), RS1000737611 (22:46356691 C>A,T), RS1000792881 (22:46347970 T>C), RS1000806935 (22:46357514 G>A), RS1000926927 (22:46348317 C>T)

Disease associations

OMIM: gene MIM:610230 | disease phenotypes: MIM:580000, MIM:613070

GenCC curated gene-disease

Disease	Classification	Inheritance
acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins	Definitive	Autosomal recessive
mitochondrial myopathy with reversible cytochrome C oxidase deficiency	Supportive	Mitochondrial

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR
Leigh syndrome	Moderate	AR

Mondo (4): deafness, aminoglycoside-induced (MONDO:0010799), acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (MONDO:0013111), long QT syndrome (MONDO:0002442), mitochondrial myopathy with reversible cytochrome C oxidase deficiency (MONDO:0010780)

Orphanet (2): Mitochondrial non-syndromic sensorineural deafness with susceptibility to aminoglycoside exposure (Orphanet:168609), Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (Orphanet:217371)

HPO phenotypes

51 total (30 of 51 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000158	Macroglossia
HP:0000218	High palate
HP:0000707	Abnormality of the nervous system
HP:0000737	Irritability
HP:0000952	Jaundice
HP:0001252	Hypotonia
HP:0001265	Hyporeflexia
HP:0001290	Generalized hypotonia
HP:0001324	Muscle weakness
HP:0001392	Abnormality of the liver
HP:0001403	Macrovesicular hepatic steatosis
HP:0001414	Microvesicular hepatic steatosis
HP:0001427	Mitochondrial inheritance
HP:0001522	Death in infancy
HP:0001626	Abnormality of the cardiovascular system
HP:0002013	Vomiting
HP:0002033	Poor suck
HP:0002098	Respiratory distress
HP:0002151	Increased circulating lactate concentration
HP:0002194	Delayed gross motor development
HP:0002240	Hepatomegaly
HP:0002904	Hyperbilirubinemia
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003073	Hypoalbuminemia
HP:0003128	Lactic acidosis
HP:0003198	Myopathy
HP:0003200	Ragged-red muscle fibers
HP:0003215	Dicarboxylic aciduria
HP:0003234	Decreased circulating carnitine concentration

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST012489_152	Heel bone mineral density x serum urate levels interaction	4.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
C564013	Deafness, Aminoglycoside-Induced (supp.)

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
sodium arsenite	affects expression, decreases expression, affects cotreatment, increases abundance, increases expression	4
Benzo(a)pyrene	affects methylation, increases methylation	2
Tretinoin	decreases expression	2
alpha-pinene	increases abundance, affects cotreatment, decreases expression	1
methylparaben	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance, increases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
abrine	increases expression	1
Sunitinib	decreases expression	1
Leflunomide	decreases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Air Pollutants	decreases expression, increases abundance, affects cotreatment	1
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	1
Atrazine	decreases expression	1
Doxorubicin	increases expression	1
Manganese	increases expression, affects cotreatment, decreases expression, increases abundance	1
Ozone	affects cotreatment, decreases expression, increases abundance	1
Phenobarbital	affects expression	1
Quercetin	increases expression	1
Smoke	decreases expression	1
T-2 Toxin	increases expression	1
Thiram	decreases expression	1
Tunicamycin	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression	1
Volatile Organic Compounds	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT05847556	Not specified	UNKNOWN	Video Game Hearing Tests for Remote Monitoring of Ototoxicity
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics
NCT02549664	Not specified	COMPLETED	Exercise in Genetic Cardiovascular Conditions
NCT02581241	Not specified	COMPLETED	Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome
NCT02680080	Not specified	COMPLETED	Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome
NCT02775513	Not specified	UNKNOWN	Metabolism of Patients With Genetically Caused Cardiac Arrhythmia
NCT02814981	Not specified	UNKNOWN	Hydroxyzine and Risk of Prolongation of QT Interval
NCT02876380	Not specified	COMPLETED	Prospective Identification of Long QT Syndrome in Fetal Life
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies
NCT03544918	Not specified	COMPLETED	Prevalence of Congenital Long QT Syndrome and Acquired QT Prolongation in a Hospital Cohort
NCT03642405	Not specified	UNKNOWN	Drug-induced Repolarization ECG Changes