Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

NDUFA2 : Leigh syndrome

HGNC:7685 | 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
4.5
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 4
4.5
Vanderver A et al. 2016 Jun (PMID:27159321); Perrier S et al. 2018 Feb (PMID:28857146); Hoefs SJ et al. 2008 Jun (PMID:18513682);
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 2
1
2
Loeffen JL et al. 1998 Dec 18 (PMID:9878551); Vogel RO et al. 2007 Mar 9 (PMID:17209039);
Protein Interaction 0.5 0 - 2 3 2
Loeffen JL et al. 1998 Dec 18 (PMID:9878551); Dieteren CE et al. 2008 Dec 12 (PMID:18826940); Vogel RO et al. 2007 Mar 9 (PMID:17209039);
Expression 0.5 0 - 2 1 0.5
Wirtz S et al. 2011 Apr 27 (PMID:21556144);
Functional Alteration Patient cells 1 0 - 2 2 1
1
1
Hoefs SJ et al. 2008 Jun (PMID:18513682);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2
Cell culture model 1 0 - 2 1 0.5
Curtis JM et al. 2012 Sep 21 (PMID:22822087);
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2 1 0.5
Stroud DA et al. 2016 Oct 6 (PMID:27626371);
Rescue in patient cells 1 0 - 2 1 1
Hoefs SJ et al. 2008 Jun (PMID:18513682);
Total Experimental Evidence Points (Maximum 6) 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 5 9.5 NO
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
05/20/2019
EXPERT CURATION (DATE)
Moderate
05/20/2019
EVIDENCE SUMMARY
The relationship between NDUFA2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of March 14, 2019. NDUFA2 was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2008 (Hoefs et al., PMID 18513682). Several variants in the NDUFA2 gene have been reported in ClinVar, but mostly with limited evidence of pathogenicity. Evidence supporting this gene-disease relationship includes case-level data and experimental data (PMIDs 18513682, 28857146, 27159321) to reach a case-level evidence score of 4.5 points. This gene-disease association is further supported by the function of the gene product, complex I alterations in cell lines, expression studies, and animal models reaching an experimental score of 5.0 points. The mechanism for disease is complex I deficiency. In summary, NDUFA2 is moderately associated with autosomal recessive Leigh syndrome spectrum. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 25, 2019 (SOP Version 6).