Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

COL9A1 : Stickler syndrome

MONDO:0019354 | ORPHA:828 | OMIM:614134
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
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
2.00
Nikopoulos K et al. 2011 Jul 1 (PMID:21421862); Van Camp G et al. 2006 Sep (PMID:16909383);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
1.00
1  
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
Nikopoulos K et al. 2011 Jul 1 (PMID:21421862); Van Camp G et al. 2006 Sep (PMID:16909383);
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Scores PMIDs/Notes
Points/Study Max Points Tally
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) 3
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 0.50
Sivakumaran TA et al. 2006 Jun (PMID:16718610);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
1.00
Asamura K et al. 2005 (PMID:15802199);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 1.5

 


 

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 3 1.5 4.5 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)
LIMITED
EXPERT CURATION (DATE)
LIMITED
03/26/2018
The <i>COL9A1</i> gene has been associated with Stickler syndrome in two consanguineous families. The homozygous presumed loss-of-function nonsense variants in this gene segregate with disease in six affected individuals. Splicing, gain-of-function variants in the <i>COL9A1</i> gene are associated with autosomal dominant multiple epiphyseal dysplasia (MED), while the mechanism for autosomal recessive Stickler syndrome is thought to be loss of function. This gene-disease association is supported by expression data and by animal models that recapitulate certain phenotypes of the human disease. In summary, <i>COL9A1</i> limited in its association with Stickler syndrome.