Submission Details

COL2A1 has been described in association with autosomal dominant Kniest dysplasia. The condition is characterized by "disproportionate dwarfism, cleft palate, myopia, progressive conductive hearing loss, arthropathy, and scoliosis. Radiographs of patients with Kniest dysplasia exhibit progressive skeletal changes, including splayed epiphyses and metaphyses, platyspondyly, and narrowed joint space" (PMID: 7977371). Evidence supporting this gene-disease relationship includes case level and experimental evidence. At least 11 unique variants have been described across numerous publications. Notably, the c.905C>T (p.Ala302Val), a cryptic splice donor site resulting in an in-frame loss of 7 residues, has been identified repeatedly in patients with Kniest dysplasia (PMIDs: 7977371, 25592122, 17347327, 25525159, 8893763). COL2A1 has been definitively associated with Achondrogenesis type 2-hypochondrogenesis, Platyspondylic dysplasia, Spondyloepiphyseal dysplasia, Stanescu type, Spondyloepiphyseal dysplasia congenita and Spondylometaphseal dysplasia with marked metaphyseal changes after curation by the ClinGen Skeletal Disorders GCEP. This gene has also been associated with Spondyloperipheral dysplasia, SED with metatarsal shortening (Czech dysplasia), Stickler syndrome type I, and Dysplasia of the proximal femoral epiphyses, which will be assessed separately (PMID: 31633310). In summary, COL2A1 is definitively associated with Kniest 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 Skeletal Disorders Gene Curation Expert Panel on 9/1/21 (SOP version 8).

COL2A1 has been described in association with autosomal dominant Kniest dysplasia. The condition is characterized by "disproportionate dwarfism, cleft palate, myopia, progressive conductive hearing loss, arthropathy, and scoliosis. Radiographs of patients with Kniest dysplasia exhibit progressive skeletal changes, including splayed epiphyses and metaphyses, platyspondyly, and narrowed joint space" (PMID: 7977371). 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. Evidence supporting this gene-disease relationship includes case level and experimental evidence. At least 11 unique variants have been described across numerous publications. Notably, the c.905C>T (p.Ala302Val), a cryptic splice donor site resulting in an in-frame loss of 7 residues, has been identified repeatedly in patients with Kniest dysplasia (PMIDs: 7977371, 25592122, 17347327, 25525159, 8893763). In summary, COL2A1 is definitively associated with Kniest 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 Skeletal Disorders Gene Curation Expert Panel on 9/1/21 (SOP version 8).