Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

COL11A2 : otospondylomegaepiphyseal dysplasia

HGNC:2187 | MONDO_0008975
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 7
Vikkula M et al. 1995 Feb 10 (PMID:7859284); Temtamy SA et al. 2006 Jun 1 (PMID:16637051); Harel T et al. 2005 Jan 1 (PMID:15558753); Kayserili H et al. 2011 Jan (PMID:21204229); Tokgöz-Yılmaz S et al. 2011 Mar (PMID:21208667); Melkoniemi M et al. 2000 Feb (PMID:10677296);
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) 12
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 1 2 2
Li SW et al. 2001 Oct (PMID:11668593);
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 12 3.5 15.5 YES
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 otospondylomegaepiphyseal dysplasia and assessed separately. This assessment focuses on its association to autosomal recessive otospondylomegaepiphyseal dysplasia. The COL11A2 gene was first associated with autosomal recessive otospondylomegaepiphyseal dysplasia in humans as early as 1995 (Vikkula et al.). At least 8 variants in 8 probands (missense, nonsense, frameshift) have been reported in humans (PMIDs: 7859284, 16637051, 15558753, 21204229, 21208667, 10677296) with all variants demonstrated or expected to lead to the expression of an altered protein, consistent with a dominant-negative impact on the triple chain collagen molecule. For example, most reported variants affect the Gly-X-Y triplet of the protein. Several of these variants segregated with disease in 10 additional family members. More genetic evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The gene-disease association is supported by a homozygous mouse model (Li et al. 2001). In summary, COL11A2 is definitively associated with autosomal recessive otospondylomegaepiphyseal dysplasia. This classification was approved by the ClinGen Hearing Loss Working Group on 12/20/2018.