Gene Validity Curation

COL9A3 - Stickler syndrome

Gene: COL9A3 (HGNC:2219)
Classification - 09/17/2019
Disease: Stickler syndrome (MONDO_0019354)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Hearing Loss EP
Evidence Summary: COL9A3 was reported in relation to autosomal recessive Stickler syndrome in 2014 (Faletra et al., 24273071). At least 3 unique nonsense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 3 probands in 3 publications (PMID: 24273071, 30450842, 31090205). The mechanism of disease is unknown. Of note, this gene has also been implicated in multiple epiphyseal dysplasia, susceptibility to intervertebral disc disease, and non-syndromic hearing loss. These have been or will be assessed separately. This gene-disease association is supported by expression studies and animal models. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Hearing Loss Working Group on 9/17/19 (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 3
4
4
Hanson-Kahn A et al. 2018 Dec (PMID:30450842); Faletra F et al. 2014 Jan (PMID:24273071); Nixon TRW et al. 2019 Aug (PMID:31090205);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 0 0  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 1.45 1
Faletra F et al. 2014 Jan (PMID:24273071);
Total Summed LOD Score 1.45    
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
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
1.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 3 1.5
Usami S et al. 2008 Jun 12 (PMID:18448257); Asamura K et al. 2005 (PMID:15802199); Goldstein O et al. 2010 Aug (PMID:20686772);
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 2 2
Goldstein O et al. 2010 Aug (PMID:20686772);
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) 3.5

 


 

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 3.5 7.5 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
09/20/2019
EXPERT CURATION (DATE)
Moderate
09/17/2019
EVIDENCE SUMMARY
COL9A3 was reported in relation to autosomal recessive Stickler syndrome in 2014 (Faletra et al., 24273071). At least 3 unique nonsense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 3 probands in 3 publications (PMID: 24273071, 30450842, 31090205). The mechanism of disease is unknown. Of note, this gene has also been implicated in multiple epiphyseal dysplasia, susceptibility to intervertebral disc disease, and non-syndromic hearing loss. These have been or will be assessed separately. This gene-disease association is supported by expression studies and animal models. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Hearing Loss Working Group on 9/17/19 (SOP Version 7).