COL1A2 has been repeatedly described in association with autosomal dominant Osteogenesis Imperfecta (OI) Type 3. OI Type 3 is characterized by the presence of severe bone fragility, multiple fractures present at birth, bone malformations, short stature, dentinogenesis imperfecta, macrocephaly, hearing loss, and blue sclerae that can normalize with age. At least 15 missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. 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 into multiple disease entities, osteogenesis imperfecta type II (OMIM:166210), osteogenesis imperfecta type III (OMIM:259420), osteogenesis imperfecta, type IV (OMIM:166220), Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2 (OMIM:619120), Ehlers-Danlos syndrome, arthrochalasia type, 2 (OMIM:617821), Ehlers-Danlos syndrome, cardiac valvular type (OMIM:225320), and Osteoporosis, postmenopausal. Variants in this gene have been reported in at least 21 probands across 10 papers.(PMIDs: 8081394, 7860070, 7749416, 19208385, 19208385, 8950681, 10807697, 24668929, 34306033, 10408781). 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 animal models (PMID: 8446583). OIM mice demonstrate phenotypic and biochemical features similar to those seen in moderate to severe human OI Type 3. In summary, there is definitive evidence to support the relationship between COL1A2 and autosomal dominant Osteogenesis Imperfecta type 4. 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 3/2/22 (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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