COL1A2 was first reported in relation to autosomal dominant Ehlers-Danlos Syndrome Arthroclasaia Type, 2 (EDSARTH2) in 1985 (Eyre et al., PMID:2993307). Ehlers-Danlos Syndrome Arthroclasaia Type, 2 is an autosomal dominant generalized connective tissue disorder affecting primarily the skin, joints, and blood vessel walls. EDSARTH2 is distinguished from other types of EDS by the frequency of congenital hip dislocation and extreme joint laxity with recurrent incomplete or partial dislocation of joints, and minimal skin involvement. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, osteogenesis imperfecta type II (OMIM:166210), osteogenesis imperfecta type III (OMIM:259420), osteogenesis imperfecta, type IV (OMIM:166220), Ehlers-Danlos syndrome, arthrochalasia type, 2 (OMIM:617821), Ehlers-Danlos syndrome, cardiac valvular type (OMIM:225320), Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2 (OMIM: 619120), and Osteoporosis, postmenopausal (OMIM:166710). The split curations have been curated separately. Six splice site variants that have been reported in 14 probands in 7 publications (PMIDs: 2454224, 1712342, 1577745, 1556139, 9295084, 24440294, 32091183) are included in this curation. The mechanism of pathogenicity is known to be loss of function. Variants seen typically cause skipping of exon 6, eliminating the N-proteinase cleavage site necessary for proper collagen processing. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by expression studies models (PMIDs: 1577745, 1556139). In summary, there is definitive evidence to support the relationship between COL1A2 and autosomal dominant Ehlers-Danlos Syndrome Arthroclasaia Type, 2. 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 11/2/22 (SOP Version 9).
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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