Gene Validity Curation

EARS2 - Leigh syndrome

Gene: EARS2 (HGNC:29419)
Classification - 03/19/2020
Disease: Leigh syndrome (MONDO_0009723)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Mitochondrial Diseases EP
Evidence Summary: The relationship between EARS2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of February 26, 2020. The EARS2 gene encodes mitochondrial glutamyl-tRNA synthetase 2, one of the mitochondrial aminoacyl-tRNA synthetases, which function in mitochondrial translation by catalyzing the attachment of amino acids to their cognate tRNAs. Defects in tRNA charging can result in impaired synthesis of protein subunits of oxidative phosphorylation complexes I, III, IV, and V. The EARS2 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2012 (PMID: 22492562). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included twelve unique variants identified in eight cases from four publications (PMIDs: 22492562, 27206875, 27571996, 27117034). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function and functional alterations in patient cells (PMIDs: 29980628, 27977873, 22492562). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 26, 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 5
10
12
Steenweg ME et al. 2012 May (PMID:22492562); Oliveira R et al. 2016 Aug 30 (PMID:27571996); Güngör O et al. 2016 Oct (PMID:27117034);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
2
Steenweg ME et al. 2012 May (PMID:22492562); Şahin S et al. 2016 Jun 15 (PMID:27206875);
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) 12
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
Boczonadi V et al. 2018 July 20 (PMID:29980628);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
1
1
Steenweg ME et al. 2012 May (PMID:22492562);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4
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) 3

 


 

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 12 3 15 YES
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)
Definitive
03/19/2020
EXPERT CURATION (DATE)
Definitive
03/19/2020
EVIDENCE SUMMARY
The relationship between EARS2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of February 26, 2020. The EARS2 gene encodes mitochondrial glutamyl-tRNA synthetase 2, one of the mitochondrial aminoacyl-tRNA synthetases, which function in mitochondrial translation by catalyzing the attachment of amino acids to their cognate tRNAs. Defects in tRNA charging can result in impaired synthesis of protein subunits of oxidative phosphorylation complexes I, III, IV, and V. The EARS2 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2012 (PMID: 22492562). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included twelve unique variants identified in eight cases from four publications (PMIDs: 22492562, 27206875, 27571996, 27117034). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function and functional alterations in patient cells (PMIDs: 29980628, 27977873, 22492562). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 26, 2020 (SOP Version 7).