Submission Details

The COL11A2 gene has been reported in association with multiple conditions and inheritance patterns. Per criteria outlined 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.