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 II is also known as lethal OI, and is characterized by bone fragility, perinatal fractures, severe bowing of long bones, blue sclerae in some cases, undermineralization, and death in the perinatal period due to respiratory insufficiency (Sillence et al. 1979; PMID: 458828). COL1A1 variants associated with OI Type II are not always 100% predictive of the disease because of genetic modifiers, and therefore long term survival and involvement in other types of OI can be seen with certain variants implicated in this disease. Evidence supporting this gene-disease relationship includes case-level and experimental data. At least 18 unique variants (missense, in-frame deletions and duplications, and one frameshift variant not predicted to cause NMD) have been identified in OI Type II patients in 10 publications (PMIDs: 21834035, 3016737, 3108247, 7679635, 8100209, 7487936, 22795119, 25958000, 11668615, 25289482). This gene-disease association is also supported by a mouse model that is compatible with the disease phenotypes, but is not a definitive model due to its use of transgene methodology (PMID: 2450280). In summary, COL1A1 is definitively associated with autosomal dominant Osteogenesis Imperfecta Type II. 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 3/3/2021. Gene Clinical Validity Standard Operating Procedures (SOP) - Version 8.