COL1A2 was first reported in relation to autosomal dominant COL1A2-related osteogenesis imperfecta in 1988 (Wenstrup et al., PMID: 2897363). COL1A2 has been noted to be associated with multiple disease entities. 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 and assesed separately, Ehlers-Danlos syndrome and Ehlers-Danlos syndrome, cardiac valvular type. Based on overlap in phenotypic spectrums and shared modes of inheritance, osteogenesis imperfecta types 1, 2, 3, and 4 were lumped under a single disese entity, COL1A2-related osteogenesis imperfecta. This curation addresses COL1A2 in relation to osteogenesis inperfecta. Evidence supporting this gene-disease relationship includes case-level and experimental data.
At least 18 unique variants (missense, splice-site, frameshift, duplication, and small deletion) that have been reported in 20 probands in 11 publications (PMIDs: 2897363, 8257992, 11836364, 18375391, 8081394, 34306033, 1301191, 22795120, 9923651,19594296, 35052464) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Variants in this gene segregated with disease in 6 additional family members (PMIDs: 18375391). This gene-disease relationship is also supported by functional assay, protein interaction, and animal models (PMIDs: 8786074, 32482890, 19594296, 8446583, 30579604). In summary, there is definitive evidence to support the relationship between COL1A2 and autosomal dominant COL1A2-related osteogenesis Imperfecta. 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 December 5th, 2022 (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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