The COL11A2 gene was first associated with autosomal dominant nonsyndromic hearing loss in humans as early as 1999 (McGuirt et al., 1999, PMID:10581026). 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 for nonsyndromic hearing loss and otospondylomegaepiphyseal dysplasia and assessed them separately. This curation focuses on its relationship with autosomal dominant nonsyndromic hearing loss. At least 18 unique variants (missense, nonsense, synonymous, splice-site, and deletion) in 18 probands have been reported in humans (PMIDs:10581026, 23990876, 23967202, 26969326, 27911912, 27610647, 31152317, 33297549, 31045651, 33229591, 33597575, 36515421, 36703223, 36597107, doi:10.1007/s13258-016-0440-4). Variants in this gene segregated with disease in 41 additional family members (PMID:10581026). This gene-disease relationship is also supported by an expression study (PMID:15141750). In summary, there is definitive evidence to support the relationship between COL11A2 and autosomal dominant nonsyndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
This gene-disease pair was originally evaluated by the Hearing Loss GCEP on 12/20/2018. It was re-evaluated on 11/15/2023. As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of new genetic evidence (PMIDs:23990876, 23967202, 26969326, 27911912, 27610647, 31152317, 33297549, 31045651, 33229591, 33597575, 36515421, 36703223, 36597107, doi:10.1007/s13258-016-0440-4) although no new experimental evidence was included. This classification was approved by the ClinGen Hearing Loss GCEP on the meeting date 11/15/2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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