COL2A1 has been described in association with autosomal dominant Spondyloepiphyseal dysplasia congenita (SEDC). The condition is characterized by "disproportionate short stature, abnormal epiphyses, and flattened vertebral bodies. Skeletal features are manifested at birth and evolve with time. Other features include myopia and/or retinal degeneration with retinal detachment and cleft palate" (PMID:1971141). Evidence supporting this gene disease relationship includes case level and experimental evidence. Notably the c.2965C>T (p.Arg989Cys) variant (legacy name Arg789Cys) in COL2A1 has been identified repeatedly in patients with SEDC. Pathogenicity of this variant is supported by functional evidence and a mouse model. The p.Arg989Cys variant was scored 3 times in this curation in unrelated probands, although more occurrences are available in the literature. More cases supporting the gene-disease relationship between COL2A1 and SEDC have been published, but the maximum score for genetic evidence (12 pts.) has been reached. At least ten unique missense variants have been described across numerous publications. COL2A1 has been definitively associated with Achondrogenesis type 2-hypochondrogenesis, platyspondylic dysplasia, Spondyloepiphyseal dysplasia, Stanescu type, and Spondylometaphseal dysplasia with marked metaphyseal changes after curation by the ClinGen Skeletal Disorders GCEP. This gene has also been associated with Kniest dysplasia, Spondyloperipheral dysplasia, SED with metatarsal shortening (Czech dysplasia), Stickler syndrome type I, Dysplasia of the proximal femoral epiphyses), which will be assessed separately (PMID: 31633310). In summary, COL2A1 is definitively associated with Spondyloepiphyseal dysplasia congenita. 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 6/7/2021 (SOP version 8).
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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