Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

FOXRED1 : Leigh syndrome

HGNC:26927 | 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 1
Calvo SE et al. 2010 Oct (PMID:20818383);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
Fassone E et al. 2015 Jul 15 (PMID:26022995);
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
Formosa LE et al. 2015 May 15 (PMID:25678554);
Protein Interaction 0.5 0 - 2 1 1
Formosa LE et al. 2015 May 15 (PMID:25678554);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 2
Zurita Rendón O et al. 2016 Aug 15 (PMID:27215383); Apatean D et al. 2019 Jun (PMID:31065540);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 1.5 1.5
Salama M et al. 2019 Feb (PMID:30392038);
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) 5



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 4 5 9 NO
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between FOXRED1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of October 14, 2019. Variants in FOXRED1 were first reported in humans with Leigh syndrome spectrum as early as 2010 (PMID: 20818383). Four unique variants predicted to cause a loss of or reduced function of the protein have been reported in ClinVar, suggesting loss of function is the mechanism of disease for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Two probands with confirmed FOXRED1 mutations demonstrating a Leigh syndrome spectrum phenotype have been reported in 2 publications (PMIDs: 26022995, 20818383) to reach a case-level evidence score of 4. This gene-disease association is further supported by FOXRED1’s protein interaction and shared function with other genes associated with Leigh syndrome spectrum, mitochondrial alterations in patient cell lines, and a FOXRED1 mouse model exhibiting a neuropathological and behavioral phenotype, reaching an experimental score of 5 pts. In summary, there is moderate evidence to support the relationship between FOXRED1 and autosomal recessive Leigh syndrome spectrum. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 14, 2019 (SOP Version 7).