Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

COL11A2 : nonsyndromic genetic deafness

HGNC:2187 | MONDO_0019497
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 2
Sloan-Heggen CM et al. 2015 Dec (PMID:26445815);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
Chakchouk I et al. 2015 Aug (PMID:25633957); Chen W et al. 2005 Oct (PMID:16033917);
Segregation Evidence   Summed LOD Family Count 2.3 2.3  
Candidate gene sequencing 2.66 1
Chen W et al. 2005 Oct (PMID:16033917);
Exome/genome or all genes sequenced in linkage region 2.68 1
Chakchouk I et al. 2015 Aug (PMID:25633957);
Total Summed LOD Score 5.34    
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) 4.8
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 1 0.5
Shpargel KB et al. 2004 Apr (PMID:15141750);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 1 1
Masaki K et al. 2009 Jun 3 (PMID:19486694);
Models Non-human model organism 2 0 - 4 4
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) 1.5



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 4.8 1.5 6.3 NO
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The COL11A2 gene has been reported in association with multiple conditions and inheritance patterns. Per criteria outlines by the ClinGen Lumping and Splitting Working Group, we found differences in variant type, inheritance pattern, and phenotype within reported COL11A2 cases. Therefore we have split curations by inheritance pattern and again by nonsyndromic hearing loss and Stickler syndrome and assessed separately. This assessment focuses on its association to autosomal recessive nonsyndromic hearing loss. The COL11A2 gene was first associated with this disease in humans as early as 2005 (Chen et al.). At least 4 missense variants in 4 probands have been reported in humans (PMIDs: 25633957, 16033917, MORL unpublished data). Variants in this gene segregated with disease in 10 additional family members. This gene-disease association is supported by relevant expression and functional studies. 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 12/20/2018.