Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

COL11A2 : otospondylomegaepiphyseal dysplasia

HGNC:2187 | MONDO_0008975
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
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 5 7.5 7.5
Vikkula M et al. 1995 Feb 10 (PMID:7859284); Sirko-Osadsa DA et al. 1998 Feb (PMID:9506662); Vuoristo MM et al. 2004 Oct 1 (PMID:15372529); Iwasa Y et al. 2015 May (PMID:25780254); Jakkula E et al. 2005 Jun (PMID:15922184);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 2
Pihlajamaa T et al. 1998 Nov 2 (PMID:9805126); van Beelen E et al. 2012 Sep (PMID:22796475);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 6.02 2
Vikkula M et al. 1995 Feb 10 (PMID:7859284); Iwasa Y et al. 2015 May (PMID:25780254);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 6.02    
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
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) 0.5



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 0.5 12.5 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 dominant otospondylomegaepiphyseal dysplasia . The COL11A2 gene was first associated with autosomal dominant otospondylomegaepiphyseal dysplasia in humans as early as 1995 (Vikkula et al.). At least 7 variants in 7 probands (missense, in-frame intel, splice site, nonsense, small deletion) have been reported in humans (PMIDs: 7859284, 9506662, 9805126, 15372529, 22796475, 25780254, 15922184) with all variants demonstrated or expected to lead to the expression of an altered protein, consistent with a dominant-negative impact on the triple chains collagen molecule. For example, three of the reported variants were shown by RT-PCR to cause an in-frame exon skipping. Other reported variants affect the Gly-X-Y triplet of the protein. Several of these variants segregated with disease in 27 additional family members. In summary, COL11A2 is definitely associated with autosomal dominant otospondylomegaepiphyseal dysplasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 12/20/18.