Submission Details

COL2A1 was first reported in relation to autosomal dominant dysplasia of the proximal femoral epiphyses in 2005 (Liu et al., PMID: 15930420). Dysplasia of the proximal femoral epiphyses is a relatively milder form of the other skeletal disorders associated with COL2A1. It is generally characterized by avascular necrosis of the femoral head, cystic changes of the femoral head, and/or sclerosis of the femoral head. Cases include patients diagnosed with multiple epiphyseal dysplasia with severe proximal femoral dysplasia, avascular necrosis of the femoral head (ANFH), Legg-Calvé-Perthes Disease (LCPD), and Namaqualand hip dysplasia (NHD). 9 variants (missense) that have been reported in 14 probands in 12 publications (PMIDs: 15930420, 17394019, 18512791, 20131279, 24949742, 25050885, 25124518, 29750297, 30740902, 32071555, 33404007, 34088323) are included in this curation. Notably, COL2A1 has been definitively associated with Achondrogenesis type 2-hypochondrogenesis, Platyspondylic dysplasia, Spondyloepiphyseal dysplasia, Stanescu type, Spondyloepiphyseal dysplasia congenita, Kniest dysplasia, spondyloperipheral dysplasia, and Stickler syndrome type I as well as moderately with SED with metatarsal shortening (Czech Dysplasia) after curation by the ClinGen Skeletal Disorders GCEP. The exact mechanism of pathogenicity is currently unknown, although dysplasia of the proximal femoral epiphyses is commonly associated with p.G393S, p.G717S, and p.G1170S. This gene-disease association is also supported by experimental evidence (expression and functional alteration studies) (PMIDs: 3033664, 7806485, 20204389). In summary, there is definitive evidence supporting the relationship between COL2A1 and dysplasia of the proximal femoral epiphyses. 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 Skeletal Disorders GCEP on the meeting date April 4, 2022 (SOP Version 10).

COL2A1 was first reported in relation to autosomal dominant dysplasia of the proximal femoral epiphyses in 2005 (Liu et al., PMID: 15930420). Dysplasia of the proximal femoral epiphyses is a relatively milder form of the other skeletal disorders associated with COL2A1. It is generally characterized by avascular necrosis of the femoral head, cystic changes of the femoral head, and/or sclerosis of the femoral head. Cases include patients diagnosed with multiple epiphyseal dysplasia with severe proximal femoral dysplasia, avascular necrosis of the femoral head (ANFH), Legg-Calvé-Perthes Disease (LCPD), and Namaqualand hip dysplasia (NHD). 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. 9 variants (missense) that have been reported in 14 probands in 12 publications (PMIDs: 15930420, 17394019, 18512791, 20131279, 24949742, 25050885, 25124518, 29750297, 30740902, 32071555, 33404007, 34088323) are included in this curation. The exact mechanism of pathogenicity is currently unknown, although dysplasia of the proximal femoral epiphyses is commonly associated with p.G393S, p.G717S, and p.G1170S. This gene-disease association is also supported by experimental evidence (expression and functional alteration studies) (PMIDs: 3033664, 7806485, 20204389). In summary, there is definitive evidence supporting the relationship between COL2A1 and dysplasia of the proximal femoral epiphyses. 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 Skeletal Disorders GCEP on the meeting date April 4, 2022 (SOP Version 10).