Gene Validity Curation

BCS1L - Leigh syndrome

Gene: BCS1L (HGNC:1020)
Classification - 09/19/2019
Disease: Leigh syndrome (MONDO_0009723)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Mitochondrial Diseases EP
Evidence Summary: The relationship between BCS1L and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of September 9, 2019. Variants in BCS1L were first reported in humans with Leigh syndrome spectrum in 2001 (PMID: 11528392). 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. One proband with BCS1L a homozygous pathogenic variant with Leigh syndrome spectrum has been reported in the 2001 publication (PMID: 11528392) to reach a case-level evidence score of 1.5. This gene-disease association is further supported by BCS1L protein interaction with other genes associated with Leigh syndrome spectrum, BCS1L expression in brain, mitochondrial alterations in patient cell lines, and a BCS1L mouse model exhibiting a neuropathological, biochemical, and developmental phenotype that recapitulates symptoms of Leigh syndrome spectrum reaching a experimental score of 5 pts. In summary, there is limited evidence to support the relationship between BCS1L and autosomal recessive Leigh syndrome spectrum. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on September 9, 2019 (SOP Version 7).
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
1.5
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
1.5
de Lonlay P et al. 2001 Sep (PMID:11528392);
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) 1.5
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
0.5
1
Cruciat CM et al. 1999 Oct 1 (PMID:10508156);
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 2
1.5
1.5
Tegelberg S et al. 2017 Apr 20 (PMID:28427446); Blázquez A et al. 2009 Feb (PMID:19162478);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 2.5 2.5
Tegelberg S et al. 2017 Apr 20 (PMID:28427446); Levéen P et al. 2011 Feb (PMID:21274865);
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
(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 1.5 5 6.5 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
09/19/2019
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Limited
09/19/2019
REASON(S) FOR CHANGE
The recommendation is that at least 3 probands are needed for a gene-disease clinical validity classification to be "Moderate".
EXPERT CURATION (DATE)
Limited
09/19/2019
EVIDENCE SUMMARY
The relationship between BCS1L and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of September 9, 2019. Variants in BCS1L were first reported in humans with Leigh syndrome spectrum in 2001 (PMID: 11528392). 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. One proband with BCS1L a homozygous pathogenic variant with Leigh syndrome spectrum has been reported in the 2001 publication (PMID: 11528392) to reach a case-level evidence score of 1.5. This gene-disease association is further supported by BCS1L protein interaction with other genes associated with Leigh syndrome spectrum, BCS1L expression in brain, mitochondrial alterations in patient cell lines, and a BCS1L mouse model exhibiting a neuropathological, biochemical, and developmental phenotype that recapitulates symptoms of Leigh syndrome spectrum reaching a experimental score of 5 pts. In summary, there is limited evidence to support the relationship between BCS1L and autosomal recessive Leigh syndrome spectrum. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on September 9, 2019 (SOP Version 7).