Gene Validity Curation

FARS2 - Leigh syndrome

Gene: FARS2 (HGNC:21062)
Classification - 11/25/2019
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 FARS2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of October 14, 2019. The FARS2 gene encodes mitochondrial phenylalanyl-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 oxidative phosphorylation complex protein subunits. The FARS2 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2012 (PMID: 22499341). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six unique variants identified in four cases from three publications (PMIDs: 22499341, 27549011, 29126765). No segregation data were available. Loss of function is implicated as the mechanism of disease. Of note, this gene has also been implicated in Alpers syndrome and other mitochondrial diseases which will be assessed separately. This gene-disease association is also supported by expression data, biochemical function data, and functional alterations in patient cells (PMIDs: 27977873, 26553276, 29126765). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 14, 2019 (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
4.5
Raviglione F et al. 2016 Nov (PMID:27549011);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 5
2.5
Shamseldin HE et al. 2012 Apr (PMID:22499341); Elo JM et al. 2012 Oct 15 (PMID:22833457); Walker MA et al. 2016 Aug (PMID:27095821); Vantroys E et al. 2017 Dec (PMID:29126765);
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) 4.5
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
Rahman J et al. 2017 Jan (PMID:27977873);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 1
Yang Y et al. 2016 Feb (PMID:26553276);
Functional Alteration Patient cells 1 0 - 2 2 1
1.5
1.5
Vantroys E et al. 2017 Dec (PMID:29126765);
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) 3.5

 


 

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 4.5 3.5 8 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)
Moderate
11/25/2019
EXPERT CURATION (DATE)
Moderate
11/25/2019
EVIDENCE SUMMARY
The relationship between FARS2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of October 14, 2019. The FARS2 gene encodes mitochondrial phenylalanyl-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 oxidative phosphorylation complex protein subunits. The FARS2 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2012 (PMID: 22499341). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six unique variants identified in four cases from three publications (PMIDs: 22499341, 27549011, 29126765). No segregation data were available. Loss of function is implicated as the mechanism of disease. Of note, this gene has also been implicated in Alpers syndrome and other mitochondrial diseases which will be assessed separately. This gene-disease association is also supported by expression data, biochemical function data, and functional alterations in patient cells (PMIDs: 27977873, 26553276, 29126765). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 14, 2019 (SOP Version 7).