Submission Details

COL1A1 was first reported in relation to autosomal dominant Ehlers-Danlos syndrome, classic type, 1 in 2000 (Nuytinck et al., PMID: 10739762). Classical Ehlers-Danlos syndrome is characterized by skin hyperextensibility, abnormal wound healing, and joint hypermobility. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, osteogenesis imperfecta, type I (OMIM:166200), osteogenesis imperfecta, type II (OMIM:166210), osteogenesis imperfecta, type III (OMIM:259420), osteogenesis imperfecta, type IV (OMIM:166220), Ehlers-Danlos Syndrome, arthrochalasia type, 1 (OMIM:130060), combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 (OMIM:619115), Ehlers-Danlos Syndrome, classic type, 1 (not associated with COL1A1 in OMIM), and Caffey disease (OMIM:114000). The split curations have been curated separately. One missense variant, c.934C>T (p.R312C), has been reported in 14 probands in 8 publications (PMIDs: 10739762, 17211858, 25597651, 28102596, 31323331, 31531849, 32736638, 34265140) is included in this curation. The exact mechanism of pathogenicity is currently unknown, although Ehlder-Danlos syndrome classic type 1 is generally associated with the c.934C>T (p.R312C) variant. This gene-disease association is also supported by expression evidence in skeletal, ligament, and tendon tissue (PMIDs: 19669491, 28206959). In summary, COL1A1 is moderately associated with autosomal dominant Ehlers-Danlos syndrome, classic type, 1. This classification was approved by the Skeletal Disorders Gene Curation Expert Panel on 10/3/22 (SOP version 9).