Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

ETHE1 : Leigh syndrome

HGNC:23287 | MONDO_0009723
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Mitochondrial Diseases
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

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
Barth M et al. 2010 Dec (PMID:20978941); Drousiotou A et al. 2011 Apr (PMID:20528888); Kılıç M et al. 2017 Apr (PMID:27830356); Dionisi-Vici C et al. 2016 Apr (PMID:26917598); Heberle LC et al. 2006 Jun (PMID:16376514);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 2
Mineri R et al. 2008 Jul (PMID:18593870); Yiş U et al. 2015 Jan-Mar (PMID:25878756);
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
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Uhlén M et al. 2015 Jan 23 (PMID:25613900);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 2.5
Tiranti V et al. 2009 Feb (PMID:19136963);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
Di Meo I et al. 2017 Oct (PMID:28753212);
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
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 3 15 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between ETHE1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of December 10, 2018. 34 articles were reviewed. ETHE1 was first reported in association with ethylmalonic encephalopathy in 2004 (Tiranti et al., PMID 14732903) and first associated Leigh syndrome spectrum in 2006 (Herberle et al., PMID 16376514). At least 39 unique variants predicted to cause a loss of or reduced function of the protein have been reported in ClinVar, suggesting homozygous loss of function is the mechanism of disease for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 7 probands with Leigh syndrome spectrum in 7 publications (PMID: 18593870, 20978941, 20528888, 27830356, 26917598, 16376514). This gene-disease association is supported by expression, animal model, and rescue experiments. As previously stated, this gene has been primarily associated with ethylmalonic encephalopathy (progressive disorder characterized by mutisystem involvement including chronic diarrhea, developmental delay, petechiae, and acrocyanosis). This phenotype will be assessed separately. In summary, there is definitive evidence to support the relationship between ETHE1 and autosomal recessive Leigh syndrome spectrum. More than three years have elapsed from the first proposal of the association to reach a definitive classification. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on December 10, 2018 (SOP Version 6).