GTPBP3

protein-coding

GTP binding protein 3, mitochondrial

Gene summary

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. [provided by RefSeq, Sep 2010]

MANE transcript

NM_032620.4

Inheritance

ClinVar variants

P:50U:228B:175

Top phenotype

Combined oxidative phosphorylation deficiency 23

gnomAD constraint

pLI —, LoF o/e 0.79

Max pathogenic AF

—

Genomic locus

chr19:17,334,920-17,342,731

External References & Databases

Ensembl (ENSG00000130299)

Transcript & Mutation Effects

hg38 • Region Span ~7.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between GTPBP3 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of January 13, 2020. The GTPBP3 gene encodes the GTP-binding protein 3 important for modification of the uridine at the wobble base of five mitochondrial transfer RNAs, which is critical for mitochondrial translation. The GTPBP3 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2014 (PMID: 25434004). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five variants identified in three cases in one publication (PMID: 25434004). Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function, functional alteration in non-patient cells, and model systems (PMIDs: 30459337, 29390138, 30916346, 27184967, 28732077). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 13, 2020 (SOP Version 7).

combined oxidative phosphorylation defect type 23STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014525

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *GTPBP3* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 23, 2024. The *GTPBP3* gene encodes the GTP-binding protein 3 important for modification of the uridine at the wobble base of five mitochondrial transfer RNAs (Gln, Glu, Lys, LeuUUR, Trp), which is critical for mitochondrial translation. *GTPBP3* was first reported in relation to autosomal recessive primary mitochondrial disease in 2014 (PMID: 25434004). While various names have been given to the constellation of features seen in those with *GTPBP3*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the GTPBP3 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *GTPBP3* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on January 13, 2020 (SOP v7), with a final classification of Moderate. This current curation for the association with primary mitochondrial disease includes the three cases included in the LSS curation. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 16 variants (10 missense, three frameshift, one in-frame deletion, one termination, and one splice site variant) in 12 probands from two publications (PMIDs: 25434004, 34276756). Age of onset ranges from infancy to adolescence. The outcomes are variable as some individuals live into the teens and at least one reported individual lived to the third decade (PMID: 37029485). Clinical features include hypertrophic cardiomyopathy, arrhythmia, lactic acidosis, LSS, developmental delay, seizures, feeding difficulty, and intrauterine growth restriction. Variable respiratory chain enzyme deficiencies have been reported in skeletal muscle. The mechanism of disease is loss of function. This gene-disease association is also supported by its known biochemical function of GTPBP3 in modification of mitochondrial tRNAs, functional alteration in patient and non-patient cells, rescue in patient cells, and zebrafish and worm models (PMIDs: 25434004, 29390138, 30916346, 28732077). In summary, there is definitive evidence to support the relationship between *GTPBP3* and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 23, 2024 (SOP Version 10).

combined oxidative phosphorylation defect type 23STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014525

Submitter: PanelApp Australia

combined oxidative phosphorylation defect type 23SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014525

Submitter: Orphanet

combined oxidative phosphorylation defect type 23DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014525

Submitter: G2P

Clinical Genomic Database (CGD)

Combined oxidative phosphorylation deficiency 23AR

Manifestation: Biochemical; Cardiovascular

Intervention: Cardiovascular

Rationale: Among other multi-systemic manifestations, the condition may include cardiac manifestations such as hypertrophic cardiomyopathy, and surveillance may allow early diagnosis and management

Refs: 25434004

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GTPBP3 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 514

Inborn genetic diseasesTotal: 91

not specifiedTotal: 59

Combined oxidative phosphorylation defect type 23Total: 38

GTPBP3-related disorderTotal: 14

GTPBP3-related disordersTotal: 5

See casesTotal: 4

Hypertrophic cardiomyopathyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032620.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	161 clinvar	1 clinvar	166
missense	4 clinvar	9 clinvar	222 clinvar	10 clinvar	3 clinvar	248
nonsense	8 clinvar	3 clinvar	1 clinvar			12
start loss	3 clinvar					3
frameshift	14 clinvar	7 clinvar	1 clinvar			22
splice donor/acceptor (+/-2bp)		2 clinvar				2
Total	29	21	228	171	4	453

Highest pathogenic variant AF is 0.000091575435

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032620.4	RefSeq	NP_116009.2	9	MANE Select
ENST00000324894.13	Ensembl	ENSP00000313818.7	9	MANE Select
NM_001128855.3	RefSeq	NP_001122327.1	9	Standard
NM_001195422.1	RefSeq	NP_001182351.1	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
gtpbp3	Danio rerio	Structure: post-vent region Quality: curved abnormal

Gene / Model

Organism

Observed Phenotype

gtpbp3

Danio rerio

Structure: post-vent region

Quality: curved

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

miR-targeted genes in lymphocytes - TarBase

Biological Process

tRNA wobble uridine modification
tRNA methylation
embryonic organ development

Molecular Function

GTPase activity
protein binding
GTP binding

Cellular Component

cytoplasm
mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000358792
Coding exons: 8
Length: 7816
Individuals with no LoFs: 125710
Homozygous LoFs: 0
Heterozygous LoFs: 37
Defined: 125747
p: 0.000147

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0108	343	342	1.00	0.0000222	3267
Missense (PolyPhen)		144	155.67	0.92505		1454
Synonymous	-0.425	171	164	1.04	0.0000114	1224
Loss of Function	0.826	15	18.9	0.795	0.00000106	188

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00031	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00014	0.00013	rare
South Asian	0.00026	0.00026	rare
Other	0.00034	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: GTPase involved in the 5-carboxymethylaminomethyl modification (mnm(5)s(2)U34) of the wobble uridine base in mitochondrial tRNAs. {ECO:0000305}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:25434004, ECO:0000269|PubMed:26741492}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.167

Intolerance Scores

LoFtool: 0.548
RVIS EVS: 0.22
RVIS percentile EVS: 68.44

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.900

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium