Submission Details

Classical Ehlers-Danlos syndrome (EDS) was first described as a distinct type of EDS in the 1960s (Beighton, 1968; PMID: 5682651). Childhood bruising is often the first presentation of classical EDS, which is characterized by joint laxity, fragile, hyperextensible skin, poor wound healing, widened, atrophic scars, and other manifestations of connective tissue weakness (reviewed in PMID: 20847697). The relationship of COL5A1 to autosomal dominant Ehlers-Danlos syndrome, classic type was first reported through linkage analysis in 1995 (Loughlin et al., 1995; PMID: 8541855). In 1996, the first variants were identified in patients by Nicholls et al. (PMID: 8950675) and Wenstrup et al. (PMID: 8923000). Over 150 unique variants have been reported in humans (152 Pathogenic or Likely Pathogenic variants are reported in ClinVar), the majority being frameshift, nonsense, and splicing variants resulting in null alleles, but missense and in-frame indel variants have also been reported. The mechanism for disease is primarily haploinsufficiency; the COL5A1 gene encodes the α1 chain of heterotrimeric type V collagen, which comes together with type I collagen to form collagen fibrils, thus COL5A1 haploinsufficiency is a limiting factor for sufficient production of heterotrimers, thereby compromising its regulatory role in fibril assembly (reviewed in PMID: 28192633). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Fifteen unique variants from 15 probands in 6 publications were curated (PMIDs: 9042913, 8950675, 10796876, 18972565, 8923000, 10777716). Variants in this gene segregated with disease in 19 additional family members (PMIDs: 10777716, 8923000, 18972565, 9042913). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. Experimentally, this gene-disease relationship is supported by the function of type V collagen in fibril organization (PMID: 2384532), which is consistent with the connective tissue dysfunction associated with EDS. This function is altered in patient cells (PMID: 15095409 and PMID: 14970208), but can be restored by treatment with exogenous type V collagen (PMID: 18305566). Further support is provided by a mouse model, which recapitulates many features of EDS (PMID: 16492673). In summary COL5A1 is definitively associated with autosomal dominant Ehlers-Danlos syndrome, classic type. 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 General Gene Curation Expert Panel on the meeting date March 24, 2021 (SOP Version 8).