COL2A1 has been described in association with autosomal dominant Spondylometaphyseal dysplasia (SEMD) with marked metaphyseal changes. It is is characterized by “disproportionate short stature, pectus carinatum, and scoliosis, as well as dappled metaphyses” (PMID: 7550321). This curation includes patients diagnosed with SEMD Strudwick type, SMD Algerian type, dysspondyloenchondromatosis and SMD corner fracture type. Evidence supporting with gene-disease relationship includes case level and experimental evidence. At least 17 unique missense variants have been described across numerous publications. 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, Platyspondylic dysplasia Torrance type, and Spondyloepiphyseal dysplasia congenita 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, and Dysplasia of the proximal femoral epiphyses (PMID: 31633310), which will be assessed separately. In summary, COL2A1 is definitively associated with Spondylometaphyseal 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 4/15/2021. Gene Clinical Validity Standard Operating Procedures (SOP8, revised with SOP 10).
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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