Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

COL9A2 : Stickler syndrome

HGNC:2218 | MONDO_0019354
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss
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 1
Baker S et al. 2011 Jul (PMID:21671392);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
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
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 5 2
Hartman BH et al. 2015 Mar 19 (PMID:25852475); Kamper M et al. 2017 Feb (PMID:27666725); Mitchell RE et al. 2013 Feb (PMID:23159952); Brachvogel B et al. 2013 May 10 (PMID:23530037); Asamura K et al. 2005 (PMID:15802199);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 1 0
McAlinden A et al. 2008 Jan (PMID:17721977);
Models Non-human model organism 2 0 - 4 4 4 1.5 1.5
Goldstein O et al. 2010 Aug (PMID:20686772); Kamper M et al. 2017 Feb (PMID:27666725); Asamura K et al. 2005 (PMID:15802199); Suzuki N et al. 2005 Mar (PMID:15710493);
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
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 1 3.5 4.5 NO
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
COL9A2 was first reported in relation to autosomal recessive Stickler syndrome in 2011 (Baker et al., PMID 21671392). At least 1 variant (frameshift) has been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, experimental data. Variants in this gene have been reported in at least 1 proband with Stickler syndrome in 1 publication (PMID 21671392). Variants in this gene segregated with disease in 1 additional family member. The mechanism for disease is biallelic loss of function causes the recessive, syndromic form, wheras heterozygous variants have been identified in patients with autosomal dominant epiphyseal dysplasia phenotype. This gene-disease association is supported by several expression studies investigating the collagen IX pathway in cartilage as well as several animal models with Col IX knockout generated by the disruption of Col9a1. Additionally, a canine model supports this association (Suzuki 2005, Goldstein 2010). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, we have split curations for the disease entities, epiphyseal dysplasia. This classification was approved by the ClinGen Hearing Loss Working Group on 2/19/2019 (SOP Version 5).