COL1A2 was first reported in relation to autosomal dominant Osteogenesis Imperfecta (OI) type 1 in 1986 (Sykes et al., PMID: 2873381). OI type I is a generalized connective tissue disorder characterized mainly by bone fragility and blue sclerae. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we did not find phenotypic variability between OI type I (OMIM: 166200) and osteoporosis, post-menopausal (OMIM: 166710), and have therefore lumped the two. At least 18 variants (missense, in-frame indel, and splice site) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 18 probands in 7+ publications (PMIDs: 2052622, 8829649, 15241796, 19594296, 21667357, 35052464, 35154279). 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 functional alteration, protein interactions, and animal models (PMIDs: 8786074, 32482890, 19594296). In summary, there is definitive evidence to support the relationship between COL1A2 and autosomal dominant Osteogenesis Imperfecta type 1. 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 12/5/22 (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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