Submission Details

COL1A2 was first reported in relation to autosomal dominant COL1A2-related Ehlers-Danlos Syndrome in 1985 (Eyre et al., PMID:2993307). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no differences in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities, Ehlers-Danlos syndrome, arthrochalasia type and combined osteogenesis inperfecta-Ehlers-Danlos syndrome have been lumped into a single disease entity, COL1A2-related Ehlers-Danlos syndrome. The COL1A2-related Ehlers-Danlos syndrome, cardiac valvular type was split separately due to autosomal recessive inheritance and a distinct mechanism. Notably, COL1A2 has also been associated with osteogenesis inperfecta which has been curated separately. At least 12 unique variants (missense, splice-site) that have been reported in 19 probands across 9 publications (PMIDs: 2454224, 1712342, 1577745, 1556139, 9295084, 10982177, 23692737, 24440294, 32091183) are included in this curation. The mechanism of pathogenicity is known to be loss of function. Variants seen typically cause skipping of exon 6, eliminating the N-proteinase cleavage site necessary for proper collagen processing. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is supported by expression studies (PMIDs: 1577745, 1556139). In summary, there is definitive evidence to support the relationship between COL1A2 and autosomal dominant COL1A2-related Ehlers-Danlos Syndrome. 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 November 2nd, 2022 (SOP Version 9).