GTPBP3

Summary

GTPBP3 (GTP binding protein 3, mitochondrial, HGNC:14880) is a protein-coding gene on chromosome 19p13.11, encoding 5-taurinomethyluridine-[tRNA] synthase subunit GTPB3, mitochondrial (Q969Y2). GTPase 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 locus encodes a GTP-binding protein. The encoded protein is localized to the mitochondria and may play a role in mitochondrial tRNA modification. Polymorphisms at this locus may be associated with severity of aminoglycoside-induced deafness, a disease associated with a mutation in the 12S rRNA. Alternatively spliced transcript variants encoding different isoforms have been described.

Source: NCBI Gene 84705 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 625 total — 32 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 40
• MANE Select transcript: NM_032620

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14880
Approved symbol	GTPBP3
Name	GTP binding protein 3, mitochondrial
Location	19p13.11
Locus type	gene with protein product
Status	Approved
Aliases	MSS1, THDF1, GTPBG3, MTGP1, FLJ14700
Ensembl gene	ENSG00000130299
Ensembl biotype	protein_coding
OMIM	608536
Entrez	84705

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 10 protein_coding_CDS_not_defined, 9 retained_intron, 6 protein_coding, 5 nonsense_mediated_decay

ENST00000324894, ENST00000358792, ENST00000361619, ENST00000593297, ENST00000594018, ENST00000594345, ENST00000594703, ENST00000595194, ENST00000595381, ENST00000595951, ENST00000596001, ENST00000596125, ENST00000596166, ENST00000596218, ENST00000596941, ENST00000598038, ENST00000598493, ENST00000598532, ENST00000599329, ENST00000599429, ENST00000600610, ENST00000600625, ENST00000600995, ENST00000601213, ENST00000601261, ENST00000601983, ENST00000602056, ENST00000602165, ENST00000934087, ENST00000934088

RefSeq mRNA: 4 — MANE Select: NM_032620 NM_001128855, NM_001195422, NM_032620, NM_133644

CCDS: CCDS32950, CCDS32951, CCDS56088, CCDS59364

Canonical transcript exons

ENST00000324894 — 9 exons

Exon	Start	End
ENSE00001324936	17337553	17337664
ENSE00003195750	17341478	17342731
ENSE00003533501	17338008	17338255
ENSE00003556149	17338954	17339026
ENSE00003573757	17338365	17338451
ENSE00003626532	17338539	17338741
ENSE00003665786	17339434	17339599
ENSE00003667476	17341044	17341322
ENSE00003679957	17339123	17339266

Expression profiles

Bgee: expression breadth ubiquitous, 265 present calls, max score 96.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.3818 / max 170.7441, expressed in 1763 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
174500	13.2374	1710
174499	1.1479	671
174498	0.9965	590

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	96.52	gold quality
tendon of biceps brachii	UBERON:0008188	90.43	gold quality
right adrenal gland	UBERON:0001233	89.88	gold quality
right adrenal gland cortex	UBERON:0035827	89.64	gold quality
left adrenal gland cortex	UBERON:0035825	89.47	gold quality
lower esophagus mucosa	UBERON:0035834	89.29	gold quality
right uterine tube	UBERON:0001302	89.18	gold quality
left adrenal gland	UBERON:0001234	89.12	gold quality
skin of leg	UBERON:0001511	89.09	gold quality
adrenal cortex	UBERON:0001235	88.82	gold quality
skin of abdomen	UBERON:0001416	88.78	gold quality
body of pancreas	UBERON:0001150	88.60	gold quality
metanephros cortex	UBERON:0010533	88.60	gold quality
granulocyte	CL:0000094	88.34	gold quality
body of stomach	UBERON:0001161	87.90	gold quality
minor salivary gland	UBERON:0001830	87.87	gold quality
apex of heart	UBERON:0002098	87.81	gold quality
right lobe of liver	UBERON:0001114	87.75	gold quality
oviduct epithelium	UBERON:0004804	87.69	gold quality
spleen	UBERON:0002106	87.66	gold quality
esophagus mucosa	UBERON:0002469	87.57	gold quality
zone of skin	UBERON:0000014	87.46	gold quality
right lobe of thyroid gland	UBERON:0001119	87.46	gold quality
vagina	UBERON:0000996	87.44	gold quality
left uterine tube	UBERON:0001303	87.13	gold quality
adrenal gland	UBERON:0002369	86.96	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.88	gold quality
mouth mucosa	UBERON:0003729	86.71	gold quality
right ovary	UBERON:0002118	86.66	gold quality
descending thoracic aorta	UBERON:0002345	86.59	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-7606	no	312.34
E-ANND-3	no	2.38

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

52 targeting GTPBP3, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632

Literature-anchored findings (GeneRIF, showing 11)

• GTPBP3 localizes in the mitochondria and is a deafness-associated homolog of yeast MSS1. (PMID:12370316)
• Phenotype of non-syndromic deafness associated with the mitochondrial A1555G mutation is modulated by mitochondrial RNA modifying enzymes MTO1 and GTPBP3. (PMID:15542390)
• Data show that the two most abundant GTPBP3 isoforms exhibit moderate affinity for guanine nucleotides like their bacterial homologue, MnmE, although they hydrolyze GTP at a 100-fold lower rate. (PMID:18852288)
• 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)
• Most individuals with GTPBP3 mutations developed neurological symptoms and MRI involvement of thalamus, putamen, and brainstem resembling Leigh syndrome. (PMID:25434004)
• GTPBP3 defective expression is associated with an mitochondrial-tRNA hypomodification status.GTPBP3 plays a role in the regulation of UCP2 and MCP1 proteins through AMPK signaling. (PMID:26642043)
• Low GTPBP3 expression is associated with Mitochondrial diseases in neoplasms. (PMID:28740091)
• Defects in the mitochondrial tRNA modification enzymes MTO1 and GTPBP3 promote different metabolic reprogramming through a HIF-PPARgamma-UCP2-AMPK axis. (PMID:29348686)
• Coding Variants in HOOK2 and GTPBP3 May Contribute to Risk of Primary Angle Closure Glaucoma (PMID:32397755)
• The human tRNA taurine modification enzyme GTPBP3 is an active GTPase linked to mitochondrial diseases. (PMID:33619562)
• Pathogenicity Analysis of a Novel Variant in GTPBP3 Causing Mitochondrial Disease and Systematic Literature Review. (PMID:36980825)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gtpbp3	ENSDARG00000018650
mus_musculus	Gtpbp3	ENSMUSG00000007610
rattus_norvegicus	Gtpbp3	ENSRNOG00000023403
drosophila_melanogaster	CG18528	FBGN0039189
caenorhabditis_elegans	mtcu-1	WBGENE00009557

Paralogs (1): ERAL1 (ENSG00000132591)

Protein

Protein identifiers

5-taurinomethyluridine-[tRNA] synthase subunit GTPB3, mitochondrial — Q969Y2 (reviewed: Q969Y2)

Alternative names: GTP-binding protein 3, Mitochondrial GTP-binding protein 1, tRNA modification GTPase GTPBP3, mitochondrial

All UniProt accessions (6): Q969Y2, M0QXA1, M0QYW1, M0R0S9, M0R161, M0R1X0

UniProt curated annotations — full annotation on UniProt →

Function. GTPase 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 MTO1; forms the GTPBP3-MTO1 complex composed of homodimers of GTPBP3 and MTO1. Homodimer, forms homodimer in vivo.

Subcellular location. Mitochondrion Cytoplasm.

Tissue specificity. Ubiquitously expressed.

Disease relevance. Combined oxidative phosphorylation deficiency 23 (COXPD23) [MIM:616198] An autosomal recessive mitochondrial disorder characterized by hypertrophic cardiomyopathy and/or neurologic symptoms with onset in early childhood. Disease features include hypertrophic cardiomyopathy, hypotonia, delayed psychomotor development, lactic acidosis, impaired activities of respiratory complexes I and IV, and defective translation of mitochondrial proteins. Disease severity is variable, ranging from death in early infancy to survival into the second decade of life. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Forms a homodimer in the presence of potassium.

Polymorphism. Val-250 variation may influence aminoglycoside-induced deafness (AID) [MIM:580000]. AID is characterized by deafness, varying from profond congenital hearing loss to normal hearing, and is caused by homoplasmic A1555G mutation in the mitochondrial 12S rRNA. Val-250 may affect the accuracy of codon-anticodon interaction, leading to modulate the translational efficiency and thereby affecting the severity of deafness in patients homozygous for 12S rRNA A1555G mutation.

Similarity. Belongs to the TRAFAC class TrmE-Era-EngA-EngB-Septin-like GTPase superfamily. TrmE GTPase family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q969Y2-1	1, V	yes
Q969Y2-2	2
Q969Y2-3	3, IV
Q969Y2-4	4

RefSeq proteins (4): NP_001122327, NP_001182351, NP_116009, NP_598399 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004520	GTPase_MnmE	Family
IPR005225	Small_GTP-bd	Domain
IPR006073	GTP-bd	Domain
IPR018948	GTP-bd_TrmE_N	Domain
IPR025867	MnmE_helical	Domain
IPR027266	TrmE/GcvT-like	Homologous_superfamily
IPR027368	MnmE_dom2	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR031168	G_TrmE	Domain

Pfam: PF01926, PF10396, PF12631

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (39 total): sequence variant 13, binding site 12, mutagenesis site 8, splice variant 3, transit peptide 1, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q969Y2-F1	82.25	0.56

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 (12): 284; 303–306; 374–377; 397–399; 492; 52; 112; 152; 256–263; 259; 263; 282–286

Mutagenesis-validated functional residues (8):

Position	Phenotype
136	decreased gtpase catalytic efficiency, when associated with k-142.
142	decreased gtpase catalytic efficiency, when associated with e-136.
159	small decrease in gtpase catalytic efficiency, when associated with e-431.
225	decreased gtpase catalytic efficiency, when associated with p-322.
259	strong decrease in gtpase catalytic efficiency.
315	decreased gtpase catalytic efficiency.
322	decreased gtpase catalytic efficiency, when associated with k-225.
431	small decrease in gtpase catalytic efficiency, when associated with r-159.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6787450	tRNA modification in the mitochondrion

MSigDB gene sets: 279 (showing top): GOBP_TRNA_METABOLIC_PROCESS, GOBP_RNA_METHYLATION, WEI_MYCN_TARGETS_WITH_E_BOX, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_RNA_MODIFICATION, BLALOCK_ALZHEIMERS_DISEASE_UP, MODULE_480, GOBP_MITOCHONDRIAL_RNA_PROCESSING, GOBP_TRNA_METHYLATION, GOBP_MITOCHONDRIAL_RNA_METABOLIC_PROCESS, BENPORATH_NOS_TARGETS, FISCHER_DREAM_TARGETS, GOBP_TRNA_THREONYLCARBAMOYLADENOSINE_METABOLIC_PROCESS, HAMAI_APOPTOSIS_VIA_TRAIL_DN, GOBP_METHYLATION

GO Biological Process (5): tRNA wobble uridine modification (GO:0002098), tRNA methylation (GO:0030488), mitochondrial tRNA wobble uridine modification (GO:0070899), tRNA modification (GO:0006400), tRNA processing (GO:0008033)

GO Molecular Function (6): GTPase activity (GO:0003924), GTP binding (GO:0005525), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787), tRNA 5-taurinomethyluridine synthase activity (GO:0160236)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), transferase complex (GO:1990234), GTPBP3-MTO1 complex (GO:7770010)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
tRNA processing	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	2
tRNA wobble base modification	1
RNA methylation	1
tRNA modification	1
tRNA wobble uridine modification	1
mitochondrion	1
mitochondrial tRNA modification	1
tRNA processing	1
RNA modification	1
RNA processing	1
tRNA metabolic process	1
ribonucleoside triphosphate phosphatase activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
transferase activity	1
catalytic activity, acting on a tRNA	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1
catalytic complex	1
transferase complex	1

Protein interactions and networks

STRING

1915 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GTPBP3	MTO1	Q9Y2Z2	932
GTPBP3	TRMU	O75648	858
GTPBP3	GTPBP4	Q9BZE4	785
GTPBP3	TRIT1	Q9H3H1	725
GTPBP3	PUS1	Q9Y606	673
GTPBP3	TFB1M	Q8WVM0	657
GTPBP3	ELAC2	Q9BQ52	641
GTPBP3	QTRT2	Q9H974	625
GTPBP3	CDK5RAP1	Q96SZ6	613
GTPBP3	OSGEPL1	Q9H4B0	585
GTPBP3	NFS1	Q9Y697	578
GTPBP3	TUFM	P49411	572
GTPBP3	YRDC	Q86U90	545
GTPBP3	TRMT5	Q32P41	544
GTPBP3	QTRT1	Q9BXR0	540
GTPBP3	NSUN3	Q9H649	540

IntAct

126 interactions, top by confidence:

A	B	Type	Score
ETFRF1	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
GTPBP3	PFKL	psi-mi:“MI:0915”(physical association)	0.560
GTPBP3	GNE	psi-mi:“MI:0915”(physical association)	0.560
GNE	GTPBP3	psi-mi:“MI:0915”(physical association)	0.560
PFKL	GTPBP3	psi-mi:“MI:0915”(physical association)	0.560
GTPBP3	TCF12	psi-mi:“MI:0915”(physical association)	0.560
GTPBP3	AGR2	psi-mi:“MI:0915”(physical association)	0.560
GTPBP3	DDIT4L	psi-mi:“MI:0915”(physical association)	0.560
GTPBP3	RCN1	psi-mi:“MI:0915”(physical association)	0.560
GTPBP3	PARP11	psi-mi:“MI:0915”(physical association)	0.560
AGR2	GTPBP3	psi-mi:“MI:0915”(physical association)	0.560
RCN1	GTPBP3	psi-mi:“MI:0915”(physical association)	0.560
CAPN3	GTPBP3	psi-mi:“MI:0915”(physical association)	0.560
GTPBP3	SERTAD3	psi-mi:“MI:0915”(physical association)	0.560
RALY	GTPBP3	psi-mi:“MI:0915”(physical association)	0.560
MEOX2	GTPBP3	psi-mi:“MI:0915”(physical association)	0.560
BEND7	GTPBP3	psi-mi:“MI:0915”(physical association)	0.560
DPPA4	GTPBP3	psi-mi:“MI:0915”(physical association)	0.560
INCA1	GTPBP3	psi-mi:“MI:0915”(physical association)	0.560
TBC1D3G	GTPBP3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (94): GTPBP3 (Two-hybrid), GTPBP3 (Two-hybrid), GTPBP3 (Two-hybrid), GTPBP3 (Affinity Capture-MS), GTPBP3 (Two-hybrid), GTPBP3 (Two-hybrid), GTPBP3 (Two-hybrid), GTPBP3 (Two-hybrid), GTPBP3 (Two-hybrid), GTPBP3 (Two-hybrid), GTPBP3 (Affinity Capture-MS), GTPBP3 (Affinity Capture-MS), GTPBP3 (Affinity Capture-MS), GTPBP3 (Affinity Capture-MS), GTPBP3 (Proximity Label-MS)

ESM2 similar proteins: A0A6N3IN21, A5GFZ6, A7MBC0, D3ZDK7, E1BNQ4, E2QUI9, I3LK75, P11172, P13439, P19971, P31754, P38918, P50336, P51175, P56602, P84850, Q0VGK3, Q15274, Q1JPD3, Q2KJF7, Q3T063, Q5BJY6, Q5E9M9, Q5FVR2, Q5I0M2, Q5PQQ1, Q5R514, Q5R824, Q60HD5, Q6PCB7, Q6SKR2, Q6XQN1, Q8CC86, Q8CHP8, Q8CIM3, Q8IVS8, Q8IW45, Q8IXI1, Q8JZV7, Q8N465

Diamond homologs: A1AXX6, A1KW66, A1S1G4, A1U7J3, A1UQU6, A3PNS7, A4VS81, A4WVZ0, A4YJT5, A5E8G7, A5G169, A5VA82, A5VT20, A6TG09, A6UEE9, A6WX76, A7HSK9, A8EZV9, A8F2P7, A8GPN6, A8GTM1, A8GUF3, A8I264, A8LPC2, A9CHB2, A9HE16, A9IZY1, A9M0N5, A9M9E5, B0BV57, B0CJG2, B0T6E0, B0UJI9, B1M0E0, B1ZGG9, B2IJQ3, B2VCE7, B3PS53, B3Q8A8, B4F0U0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	32
Likely pathogenic	13
Uncertain significance	262
Likely benign	258
Benign	30

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1075628	NM_032620.4(GTPBP3):c.521_527del (p.Arg174fs)	Pathogenic
1389465	NM_032620.4(GTPBP3):c.512del (p.Ala171fs)	Pathogenic
1452744	NM_032620.4(GTPBP3):c.925dup (p.Glu309fs)	Pathogenic
1457148	NM_032620.4(GTPBP3):c.665-47_665-46del	Pathogenic
1459765	NM_032620.4(GTPBP3):c.664+19G>A	Pathogenic
1802991	NM_032620.4(GTPBP3):c.187C>T (p.Arg63Ter)	Pathogenic
180615	NM_032620.4(GTPBP3):c.1375G>A (p.Glu459Lys)	Pathogenic
180616	NM_032620.4(GTPBP3):c.476A>T (p.Glu159Val)	Pathogenic
180618	NM_032620.4(GTPBP3):c.1009G>C (p.Asp337His)	Pathogenic
180619	NM_032620.4(GTPBP3):c.32_33delinsGTG (p.Gln11fs)	Pathogenic
1970782	NM_032620.4(GTPBP3):c.836del (p.Pro279fs)	Pathogenic
2032103	NM_032620.4(GTPBP3):c.1032del (p.Ser345fs)	Pathogenic
2069528	NM_032620.4(GTPBP3):c.802del (p.Leu268fs)	Pathogenic
2102551	NM_032620.4(GTPBP3):c.356del (p.Pro119fs)	Pathogenic
2254426	NM_032620.4(GTPBP3):c.12del (p.Leu5fs)	Pathogenic
2802192	NM_032620.4(GTPBP3):c.523C>T (p.Gln175Ter)	Pathogenic
280249	NM_032620.4(GTPBP3):c.1049del (p.Leu350fs)	Pathogenic
2811345	NM_032620.4(GTPBP3):c.886G>T (p.Gly296Ter)	Pathogenic
2816376	NM_032620.4(GTPBP3):c.307C>T (p.Gln103Ter)	Pathogenic
2854781	NM_032620.4(GTPBP3):c.743C>G (p.Ser248Ter)	Pathogenic
2878319	NM_032620.4(GTPBP3):c.610del (p.Ala204fs)	Pathogenic
2897080	NM_032620.4(GTPBP3):c.939del (p.Val314fs)	Pathogenic
2985940	NM_032620.4(GTPBP3):c.689A>C (p.Gln230Pro)	Pathogenic
3356193	NM_032620.4(GTPBP3):c.748del (p.Val250fs)	Pathogenic
3631718	NM_032620.4(GTPBP3):c.930_931del (p.Val311fs)	Pathogenic
3676155	NM_032620.4(GTPBP3):c.1A>G (p.Met1Val)	Pathogenic
3677731	NM_032620.4(GTPBP3):c.102_106dup (p.Ile36fs)	Pathogenic
3678863	NM_032620.4(GTPBP3):c.946C>T (p.Gln316Ter)	Pathogenic
3685514	NM_032620.4(GTPBP3):c.2T>C (p.Met1Thr)	Pathogenic
4724682	NM_032620.4(GTPBP3):c.293G>A (p.Trp98Ter)	Pathogenic

SpliceAI

1026 predictions. Top by Δscore:

Variant	Effect	Δscore
19:17338249:TTCCC:T	donor_gain	1.0000
19:17338254:AG:A	donor_loss	1.0000
19:17338255:GG:G	donor_loss	1.0000
19:17338256:G:GC	donor_loss	1.0000
19:17338257:T:G	donor_loss	1.0000
19:17338450:GG:G	donor_gain	1.0000
19:17338451:GG:G	donor_gain	1.0000
19:17338451:GGTGA:G	donor_loss	1.0000
19:17338452:G:GG	donor_gain	1.0000
19:17338452:GTGAG:G	donor_loss	1.0000
19:17338453:TGAGT:T	donor_loss	1.0000
19:17338454:G:GG	donor_loss	1.0000
19:17338684:G:GT	donor_gain	1.0000
19:17338685:C:T	donor_gain	1.0000
19:17338691:G:GT	donor_gain	1.0000
19:17338696:A:T	donor_gain	1.0000
19:17338700:C:G	donor_gain	1.0000
19:17339008:G:GT	donor_gain	1.0000
19:17339022:GCAAG:G	donor_gain	1.0000
19:17339023:CAAGG:C	donor_loss	1.0000
19:17339026:GGTG:G	donor_loss	1.0000
19:17339027:G:GA	donor_loss	1.0000
19:17339028:T:G	donor_loss	1.0000
19:17339115:A:AG	acceptor_gain	1.0000
19:17339116:C:G	acceptor_gain	1.0000
19:17339118:CACA:C	acceptor_loss	1.0000
19:17339120:C:G	acceptor_gain	1.0000
19:17339120:CA:C	acceptor_loss	1.0000
19:17339121:A:AG	acceptor_gain	1.0000
19:17339121:AGCC:A	acceptor_gain	1.0000

AlphaMissense

3109 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:17338984:T:C	F208L	0.994
19:17338986:C:A	F208L	0.994
19:17338986:C:G	F208L	0.994
19:17338577:T:C	F143L	0.993
19:17338579:C:A	F143L	0.993
19:17338579:C:G	F143L	0.993
19:17339245:A:C	S263R	0.992
19:17339247:C:A	S263R	0.992
19:17339247:C:G	S263R	0.992
19:17339244:G:C	K262N	0.991
19:17339244:G:T	K262N	0.991
19:17339243:A:T	K262M	0.990
19:17341677:T:C	F485L	0.990
19:17341679:C:A	F485L	0.990
19:17341679:C:G	F485L	0.990
19:17339242:A:G	K262E	0.988
19:17338649:G:C	A167P	0.986
19:17339225:G:A	G256E	0.986
19:17338072:A:C	S40R	0.984
19:17338074:C:A	S40R	0.984
19:17338074:C:G	S40R	0.984
19:17339532:G:C	D303H	0.984
19:17339533:A:C	D303A	0.984
19:17338099:G:C	A49P	0.983
19:17338114:A:C	S54R	0.983
19:17338116:C:A	S54R	0.983
19:17338116:C:G	S54R	0.983
19:17338641:T:C	L164P	0.982
19:17339219:T:A	V254D	0.982
19:17339243:A:C	K262T	0.982

dbSNP variants (sampled 300 via entrez): RS1000200183 (19:17334532 C>A,T), RS1000530852 (19:17333122 C>A), RS1001033609 (19:17338785 T>C), RS1001226080 (19:17336734 T>A), RS1002288989 (19:17337013 T>C), RS1002637183 (19:17335715 C>T), RS1002846176 (19:17341380 A>G), RS1003031343 (19:17336309 CAAAA>C), RS1003227343 (19:17339429 C>A,T), RS1003236434 (19:17334384 C>A,G,T), RS1003306411 (19:17340607 C>T), RS1003392969 (19:17334874 A>C,G,T), RS1003584327 (19:17339599 G>A,C), RS1004190940 (19:17339302 C>A,T), RS1004262932 (19:17335378 G>A)

Disease associations

OMIM: gene MIM:608536 | disease phenotypes: MIM:616198

GenCC curated gene-disease

Disease	Classification	Inheritance
combined oxidative phosphorylation defect type 23	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Leigh syndrome	Moderate	AR
mitochondrial disease	Definitive	AR

Mondo (2): combined oxidative phosphorylation defect type 23 (MONDO:0014525), hypertrophic cardiomyopathy (MONDO:0005045)

Orphanet (2): Combined oxidative phosphorylation defect type 23 (Orphanet:444013), Rare hypertrophic cardiomyopathy (Orphanet:217569)

HPO phenotypes

40 total (30 of 40 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000505	Visual impairment
HP:0000707	Abnormality of the nervous system
HP:0000961	Cyanosis
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001635	Congestive heart failure
HP:0001639	Hypertrophic cardiomyopathy
HP:0001644	Dilated cardiomyopathy
HP:0001667	Right ventricular hypertrophy
HP:0001712	Left ventricular hypertrophy
HP:0001716	Wolff-Parkinson-White syndrome
HP:0002151	Increased circulating lactate concentration
HP:0002415	Leukodystrophy
HP:0002878	Respiratory failure
HP:0003128	Lactic acidosis
HP:0003388	Easy fatigability
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003623	Neonatal onset
HP:0003688	Cytochrome C oxidase-negative muscle fibers
HP:0008347	Decreased activity of mitochondrial complex IV
HP:0008872	Feeding difficulties in infancy
HP:0008947	Floppy infant
HP:0010307	Stridor

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007394_2	Mitochondrial DNA copy number	1.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006312	mitochondrial DNA measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, increases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
GSK-J4	decreases expression	1
dicrotophos	increases expression	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	increases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
abrine	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, decreases expression	1
NSC 689534	affects binding, decreases expression	1
Sunitinib	increases expression	1
Arsenic	affects expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Cadmium	decreases expression, increases abundance	1
Copper	affects binding, decreases expression	1
Demecolcine	decreases expression	1
Estradiol	affects expression	1
Lead	affects methylation	1
Potassium Dichromate	decreases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
Vincristine	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C0CG	DPNJMUi001-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00879060	PHASE4	COMPLETED	Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
NCT01721967	PHASE4	COMPLETED	Ranolazine for the Treatment of Chest Pain in HCM Patients
NCT02948998	PHASE4	UNKNOWN	Evaluating the Effect of Spironolactone on Hypertrophic Cardiomyopathy
NCT03249272	PHASE4	TERMINATED	Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
NCT04133532	PHASE4	COMPLETED	Effect of Metoprolol in Post Alcohol Septal Ablation Patients With Hypertrophic Cardiomyopathy
NCT06401343	PHASE4	RECRUITING	Use of SGLT2i in noHCM With HFpEF
NCT07103655	PHASE4	NOT_YET_RECRUITING	The Therapeutic Value of Mavacamten in Hypertrophic Cardiomyopathy With Mid-to-Apical Left Ventricular Obstruction
NCT07600177	PHASE4	RECRUITING	Mavacamten to Aficamten Transition in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT00317967	PHASE3	COMPLETED	Study to Determine if Atorvastatin Reduces Size and Stiffness of Muscle in the Left Ventricle of the Heart
NCT00698074	PHASE3	UNKNOWN	Diastolic Ventricular Interaction and the Effects of Biventricular Pacing in Hypertrophic Cardiomyopathy
NCT00821353	PHASE3	COMPLETED	Antiarrhythmic Therapy Versus Catheter Ablation for Atrial Fibrillation in Hypertrophic Cardiomyopathy
NCT02431221	PHASE3	WITHDRAWN	Efficacy, Safety, and Tolerability of Perhexiline in Subjects With Hypertrophic Cardiomyopathy and Heart Failure
NCT03470545	PHASE3	COMPLETED	Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT05174416	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mavacamten in Chinese Adults With Symptomatic Obstructive HCM
NCT05182658	PHASE3	ACTIVE_NOT_RECRUITING	Empagliflozin in Hypertrophic Cardiomyopathy
NCT05186818	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM
NCT05767346	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM
NCT06116968	PHASE3	COMPLETED	An Open-Label Study of Aficamten for Chinese Patients With Symptomatic oHCM
NCT06873828	PHASE3	NOT_YET_RECRUITING	Evaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter MonitoringEvaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter Monitoring
NCT07021976	PHASE3	RECRUITING	A Phase III Trial of HRS-1893 in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT07023341	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Learn More About How Well Aficamten Works in Japanese Participants With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT07202897	PHASE3	NOT_YET_RECRUITING	LA-HCM Study : Rivaroxaban for Antithrombotic Prevention in Hypertrophic Cardiomyopathy Patients With Abnormal Left Atrial Strain.
NCT00001631	PHASE2	COMPLETED	Study of Blood Flow in Heart Muscle
NCT00001894	PHASE2	COMPLETED	A Comparison of Two Treatments: Pacemaker and Percutaneous Transluminal Septal Ablation for Hypertrophic Cardiomyopathy
NCT00001960	PHASE2	COMPLETED	Studying the Effectiveness of Pacemaker Therapy in Children Who Have Thickened Heart Muscle
NCT00011076	PHASE2	COMPLETED	Pirfenidone to Treat Hypertrophic Cardiomyopathy
NCT00035386	PHASE2	COMPLETED	Alcohol Septal Ablation in Obstructive Hypertrophic Cardiomyopathy: A Pilot Study
NCT00430833	PHASE2	UNKNOWN	CHANCE - Candesartan in Hypertrophic Cardiomyopathy
NCT00500552	PHASE2	COMPLETED	Perhexiline Therapy in Patients With Hypertrophic Cardiomyopathy
NCT01150461	PHASE2	COMPLETED	Effect of Losartan in Patients With Nonobstructive Hypertrophic Cardiomyopathy
NCT01230918	PHASE2	TERMINATED	Study to Develop a Non-invasive Marker for Monitoring Myocardial Fibrosis
NCT01447654	PHASE2	COMPLETED	Inhibition of the Renin Angiotensin System With Losartan in Patients With Hypertrophic Cardiomyopathy
NCT01696370	PHASE2	UNKNOWN	Trimetazidine Therapy in Hypertrophic Cardiomyopathy
NCT01912534	PHASE2	COMPLETED	Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM
NCT02590809	PHASE2	COMPLETED	Hypertrophic Cardiomyopathy Symptom Release by BX1514M
NCT03496168	PHASE2	COMPLETED	Extension Study of Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Previously Enrolled in PIONEER
NCT03532802	PHASE2	COMPLETED	The Effect of Metoprolol in Patients With Hypertrophic Obstructive Cardiomyopathy.
NCT03832660	PHASE2	COMPLETED	Sacubitril/Valsartan vs Lifestyle in Hypertrophic Cardiomyopathy
NCT04219826	PHASE2	COMPLETED	Dose-finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CK-3773274 in Adults With Hypertrophic Cardiomyopathy
NCT04426578	PHASE2	UNKNOWN	Role of Perhexiline in Hypertrophic Cardiomyopathy