Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

NDUFS1 : Leigh syndrome

HGNC:7707 | 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
12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 17
17
Bénit P et al. 2001 Jun (PMID:11349233); Björkman K et al. 2015 Mar (PMID:25615419); Kashani A et al. 2014 Aug (PMID:24952175); Danhauser K et al. 2011 Jun (PMID:21458341); Haack TB et al. 2012 Feb (PMID:22200994); Hoefs SJ et al. 2010 Jul (PMID:20382551); High N et al. 1992 May (PMID:1582426); Ferreira M et al. 2011 Feb (PMID:21203893);
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 2
2
2
Loeffen JL et al. 1998 Dec 18 (PMID:9878551); Ricci JE et al. 2004 Jun 11 (PMID:15186778);
Protein Interaction 0.5 0 - 2 2 1.5
Hoefs SJ et al. 2010 Jul (PMID:20382551); Loeffen JL et al. 1998 Dec 18 (PMID:9878551);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 2
1
1
Bénit P et al. 2001 Jun (PMID:11349233); Chow W et al. 1991 Nov 1 (PMID:1935949);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 0.5 1.5
Ferreira M et al. 2011 Feb (PMID:21203893); Dickinson ME et al. 2016 Sep 22 (PMID:27626380);
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
Danhauser K et al. 2011 Jun (PMID:21458341);
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 12 4.5 16.5 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)
Definitive
06/20/2019
EXPERT CURATION (DATE)
Definitive
06/20/2019
EVIDENCE SUMMARY
The relationship between NDUFS1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of March 12, 2019. NDUFS1 was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2001 (Benit et al., PMID 11349233). Several pathogenic variants have been reported in ClinVar, and loss of function is the mechanism of disease for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data (PMIDs 15824269, 21203893, 11349233, 20382551, 22200994, 19167255, 21458341, 24952175, 25615419) to reach a maximal case-level evidence score of 12 points. 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 an experimental score of 4.5 points. The mechanism for disease is complex I deficiency. In summary, NDUFS1 is definitively associated with 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 June 10, 2019 (SOP Version 6).