Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

NDUFA1 : Leigh syndrome

HGNC:7683 | MONDO_0009723
Mode of Inheritance: X-linked inheritance (HP:0001417)
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 5 5.5 5.5
Fernandez-Moreira D et al. 2007 Jan (PMID:17262856); Ogawa E et al. 2017 Sep (PMID:28429146); Miyauchi A et al. 2018 Jun (PMID:29506883); Farwell KD et al. 2015 Jul (PMID:25356970);
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
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) 5.5
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
Yadava N et al. 2004 Mar 26 (PMID:14722084);
Protein Interaction 0.5 0 - 2 2 1
Yadava N et al. 2004 Mar 26 (PMID:14722084);
Expression 0.5 0 - 2 1 0.5
Zhuchenko O et al. 1996 Nov 1 (PMID:8938439);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 1 0.5
Yadava N et al. 2004 Mar 26 (PMID:14722084);
Models Non-human model organism 2 0 - 4 4 3 6 4
Au HC et al. 1999 Apr 13 (PMID:10200266); Qi X et al. 2004 Aug (PMID:15293270); Kim C et al. 2017 Oct (PMID:28506826);
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 1 1
Uehara N et al. 2014 May (PMID:25356405);
Total Experimental Evidence Points (Maximum 6) 6



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 5.5 6 11.5 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
Score did not reach 12 points, so group agreed to keep at moderate.
The relationship between NDUFA1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of 2/28/2019. NDUFA1 was first reported in association with Leigh syndrome spectrum in 2007 (Fernandez-Moreira et al., PMID 17262856 ). Only three pathogenic variants in affected males (n=4, all inherited from unaffected mothers) predicted to cause a loss of function of the protein have been reported in ClinVar, suggesting hemizygous NDUFA1 loss of function resulting in Complex I deficiency is the disease mechanism for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data (PubMed: 17262856, 25356405, 28429146, 29506883) to reach a case-level evidence score of 5.5 pts. This gene-disease association is further supported by the function of the gene product, complex I alterations in patient cell lines, expression studies, and animal models reaching a maximal experimental score (6 points). In summary, NDUFA1 is definitively associated with X-linked recessive Leigh syndrome spectrum. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Although the total score was 11.5, the experts concluded that moderate level was more appropriate given the limited number of proven cases reported in the literature. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 25, 2019 (SOP Version 6).