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 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.