Submission Details

COL1A1 has been described in relation to autosomal dominant Osteogenesis Imperfecta (OI) Type I-IV. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in clinical phenotypic presentation and molecular mechanism between OI Types I-IV. Therefore, the following disease entities have been split: OI Type I (OMIM: 166200), OI Type II (OMIM: 166210), OI Type III (OMIM: 259420), and OI Type IV (OMIM: 166220). OI Type III is a severe type of OI characterized by progressive abnormalities of the limbs and spine, blue sclerae at birth that normalize with age, and dentinogenesis imperfecta (Sillence et al. 1979; PMID: 458828). Evidence supporting this gene-disease relationship includes case-level data. Glycine substitutions at the C-terminal of COL1A1 affect the triple helix structure formed by the pro-alpha 1(I) chains encoded by COL1A1 and the pro-alpha 2(I) chain encoded by COL2A1, and ultimately disrupt the function of type 1 collagen. Point upgrades were given in cases with glycine substitutions in order to reflect the causative nature of these variants. At least 9 missense variants, 6 of which were glycine substitutions at the C-terminal, have been identified in OI Type III patients in 7 publications (PMIDs: 2794057, 2511192, 25633413, 12870654, 11317364, 1864604, 2037280). In summary, COL1A1 is definitively associated with autosomal dominant Osteogenesis Imperfecta Type III. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This curation was approved by the Skeletal Disorders Gene Curation Expert Panel (GCEP) on 5/19/2021.