Submission Details

COL2A1 was first reported in relation to autosomal dominant Stickler syndrome type 1 in 1987 (Francomano et al., PMID: 2896625). Stickler syndrome is characterized by ocular, auditory, skeletal, and orofacial abnormalities. Most forms are identifiable by findings in the eye including high myopia, vitreoretinal degeneration, retinal detachment, and cataracts (Baker et al., PMID: 21671392). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, COL2A1-related spondyloepiphyseal dysplasia (OMIM:609162, OMIM:183900, OMIM:184254, OMIM:184250), dysplasia of the proximal femoral epiphyses (OMIM:608805, OMIM:150600), spondyloperipheral dysplasia (OMIM:271700), Stickler syndrome type 1 (OMIM:108300), Kniest dysplasia (OMIM:156550), Achondrogenesis type II (OMIM:200610), and platyspondylic skeletal dysplasia, Torrance type (OMIM:151210). The split curations have been curated separately. 10 variants (missense, nonsense, and frameshift) that have been reported in 10 probands in 7 publications (PMIDs: 1677770, 17721977, 26626311, 27408751, 31736238, 8434604, 8737653) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease association is also supported by experimental evidence (animal models and expression studies) (PMIDs: 12525971, 16546167, 3033664, 7806485). COL2A1 is expressed throughout the skeletal structure as well as throughout the eye, with expression in the vitreous space and the ganglion cell layer of the retina being most relevant to the most common phenotypes seen in patients. In summary, COL2A1 is definitively associated with autosomal dominant Stickler syndrome type 1. 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 Skeletal Disorders Gene Curation Expert Panel on 2/7/22 (SOP version 9).

COL2A1 was first reported in relation to autosomal dominant Stickler syndrome type 1 in 1987 (Francomano et al., PMID: 2896625). Stickler syndrome is characterized by ocular, auditory, skeletal, and orofacial abnormalities. Most forms are identifiable by findings in the eye including high myopia, vitreoretinal degeneration, retinal detachment, and cataracts (Baker et al., PMID: 21671392). 10 variants (missense, nonsense, and frameshift) that have been reported in 10 probands in 7 publications (PMIDs: 1677770, 17721977, 26626311, 27408751, 31736238, 8434604, 8737653) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Notably, COL2A1 has been definitively associated with Achondrogenesis type 2-hypochondrogenesis, Platyspondylic dysplasia, Spondyloepiphyseal dysplasia congenita, Kniest dysplasia, and spondyloperipheral dysplasia as well as moderately with SED with metatarsal shortening (Czech Dysplasia) after curation by the ClinGen Skeletal Disorders GCEP. This gene has also been associated with Dysplasia of the proximal femoral epiphyses (PMID: 31633310), which will be assessed separately. The mechanism of pathogenicity is known to be loss of function. This gene-disease association is also supported by experimental evidence (animal models and expression studies) (PMIDs: 12525971, 16546167, 3033664, 7806485). COL2A1 is expressed throughout the skeletal structure as well as throughout the eye, with expression in the vitreous space and the ganglion cell layer of the retina being most relevant to the most common phenotypes seen in patients. In summary, COL2A1 is definitively associated with autosomal dominant Stickler syndrome type 1. 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 Skeletal Disorders Gene Curation Expert Panel on 2/7/22 (SOP version 9).