Gene Validity Curation

GTPBP3 - Leigh syndrome

Gene: GTPBP3 (HGNC:14880)
Classification - 02/12/2020
Disease: Leigh syndrome (MONDO_0009723)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Mitochondrial Diseases EP
Evidence Summary: 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).
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 1
2
4
Kopajtich R et al. 2014 Dec 4 (PMID:25434004);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 2
2
Kopajtich R et al. 2014 Dec 4 (PMID:25434004);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 4
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
2
2
Murayama K et al. 2019 Feb (PMID:30459337);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Asano K et al. 2018 Feb 28 (PMID:29390138);
Models Non-human model organism 2 0 - 4 4 3 1.5 1.5
Chen D et al. 2019 Jun 4 (PMID:30916346); Chen D et al. 2016 Aug (PMID:27184967); Navarro-González C et al. 2017 Jul (PMID:28732077);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 4 4 8 NO
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Moderate
02/12/2020
EXPERT CURATION (DATE)
Moderate
02/12/2020
EVIDENCE SUMMARY
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).