COL2A1 was first reported in relation to autosomal dominant SED with metatarsal shortening (formerly known as Czech dysplasia) in 1993 (Williams et al., PMID: 8244341). This skeletal dysplasia is characterized by early-onset, progressive pseudorheumatoid arthritis, platyspondyly, and short third and fourth toes (Marik et al., PMID: 14730409; Kozlowski et al., PMID: 15266623). 1 variant (NM_001844.5:c.823C>T (p.Arg275Cys)) that has been reported in 17 probands in 15 publications (PMIDs: 7738948, 8244341, 8877930, 14730409, 15266623, 15593085, 16155195, 16755660, 17726487, 18553548, 19764028, 21990059, 23448908, 23928235, 32071555) are included in this curation meeting phenotypic criteria for early-onset, progressive pseudorheumatoid arthritis, platyspondyly, and short third and fourth toes. Notably, COL2A1 has been definitively associated with Achondrogenesis type 2-hypochondrogenesis, Platyspondylic dysplasia, Spondyloepiphyseal dysplasia congenita, Kniest dysplasia, and spondyloperipheral dysplasia after curation by the ClinGen Skeletal Disorders GCEP. This gene has also been associated with Stickler syndrome type I and Dysplasia of the proximal femoral epiphyses (PMID: 31633310), which will be assessed separately. COL2A1-related SED with metatarsal shortening is most frequently caused by the c.823C>T (p.Arg275Cys) variant, located at a mutational hot spot in the C-propeptide of COL2A1 specific to SED with metatarsal shortening. This gene-disease association is also supported by experimental evidence (expression studies) (PMIDs: 3033664, 7806485). COL2A1 is shown to be expressed in the marrow cells, osteoblasts, fibroblasts and some osteocytes, chondrocytes in the otic capsule, and the extracellular matrix surrounding chondrocytes in cartilage. In summary, COL2A1 is moderately associated with autosomal dominant SED with metatarsal shortening (formerly known as Czech dysplasia). This classification was approved by the Skeletal Disorders Gene Curation Expert Panel on 12/6/21 (SOP version 9).
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