Submission Details

COL1A1 has been described in relation to autosomal dominant Osteogenesis Imperfecta (OI) Types 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 I is the mildest of Types I-IV and is characterized by “blue sclerae, normal stature, bone fragility without significant deformity and osteopenia” and fibroblasts of affected individuals "produce about half the expected amount of structurally normal type I collagen,” indicating reduced protein as the mechanism of disease (Willing et al. 1990, PMID: 2295701). Evidence supporting this gene-disease relationship includes case-level, segregation, and experimental data. At least 21 unique null variants (nonsense, splice site, frameshift, and large deletions) have been identified in OI Type I patients in 8 publications (PMIDs: 2295701, 7942841, 8808594, 32165296, 28901398, 31653500, 26478226, 26634493). This gene-disease association is also supported by an animal model that recapitulates the disease’s phenotypes and mechanism (PMID: 31369917). In summary, COL1A1 is definitively associated with autosomal dominant Osteogenesis Imperfecta Type I. 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 1/19/2021. Gene Clinical Validity Standard Operating Procedures (SOP) - SOP8.