Gene Validity Curation

GFM1 - Leigh syndrome

Gene: GFM1 (HGNC:13780)
Classification - 12/19/2019
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 GFM1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of December 9, 2019. The GFM1 gene encodes mitochondrial elongation factor G1 (also referred to as EFG1 or EGF1), that is one of three nuclear-encoded elongation factors and plays an important role in mitochondrial translation. The GFM1 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2007 (PMID: 17160893). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six unique variants identified in three unrelated cases from three publications; all cases were compound heterozygous for a predicted null variant and a missense variant (PMIDs: 217160893, 23430926, 25852744). No segregation data were available. Loss of function is implicated as the mechanism of disease. Of note, this gene has also been implicated in other mitochondrial diseases (including fatal infantile hepatopathy) which will be assessed separately. This gene-disease association is also supported by known biochemical function, expression, functional alteration in patient cells, functional alteration in non-patient cells, rescue in patient cells, and rescue in animal models (PMIDs: 17160893, 18853439, 27977873, 21364917, 25852744). 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 December 9, 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 3
6
6
Valente L et al. 2007 Jan (PMID:17160893); Balasubramaniam S et al. 2011 Dec 21 (PMID:23430926); Brito S et al. 2015 Mar 23 (PMID:25852744);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
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) 6
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
1.5
2
Rahman J et al. 2017 Jan (PMID:27977873);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Pontén F et al. 2008 Dec (PMID:18853439);
Functional Alteration Patient cells 1 0 - 2 2 1
1
1.5
Brito S et al. 2015 Mar 23 (PMID:25852744);
Non-patient cells 0.5 0 - 1 1 0.5
Valente L et al. 2007 Jan (PMID:17160893);
Models Non-human model organism 2 0 - 4 4 1
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
0.5
Trivigno C et al. 2011 Feb 25 (PMID:21364917);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2 1 0.5
Valente L et al. 2007 Jan (PMID:17160893);
Total Experimental Evidence Points (Maximum 6) 4.5

 


 

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 6 4.5 10.5 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
12/19/2019
EXPERT CURATION (DATE)
Moderate
12/19/2019
EVIDENCE SUMMARY
The relationship between GFM1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of December 9, 2019. The GFM1 gene encodes mitochondrial elongation factor G1 (also referred to as EFG1 or EGF1), that is one of three nuclear-encoded elongation factors and plays an important role in mitochondrial translation. The GFM1 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2007 (PMID: 17160893). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six unique variants identified in three unrelated cases from three publications; all cases were compound heterozygous for a predicted null variant and a missense variant (PMIDs: 217160893, 23430926, 25852744). No segregation data were available. Loss of function is implicated as the mechanism of disease. Of note, this gene has also been implicated in other mitochondrial diseases (including fatal infantile hepatopathy) which will be assessed separately. This gene-disease association is also supported by known biochemical function, expression, functional alteration in patient cells, functional alteration in non-patient cells, rescue in patient cells, and rescue in animal models (PMIDs: 17160893, 18853439, 27977873, 21364917, 25852744). 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 December 9, 2019 (SOP Version 7).