Submission Details

COL5A2 was first reported in relation to autosomal dominant Ehlers-Danlos syndrome (EDS), classic type, in 1998 (Michalickova et al, PMID: 9425231; Richards et al, PMID: 9783710). First described by Beighton in 1968, classic EDS (formerly known as EDS type I or “gravis” and type II or “mitis”) is a connective tissue disorder characterized by joint hypermobility, skin hyperextensibilty, and skin fragility leading to atrophic scarring (reviewed in Bowen et al, 2017, PMID: 28192633; Malfait et al, 2018, PMID 20301422). This curation includes nineteen unique variants (splicing variants causing in frame deletions, missense variants, one in frame deletion/insertion, and a 3’ terminal frameshift not expected to undergo nonsense-mediated decay) that have been reported in nineteen probands meeting clinical criteria for classic EDS in six publications (Michalickova et al, 1998, PMID: 9425231; Richards et al, 1998, PMID: 9783710; Malfait et al, 2005, PMID: 15580559; Symoens et al, 2012, PMID: 22696272; Ritelli et al, 2013, PMID: 23587214, Watanabe et al, 2016, PMID: 27656288). Of note, none of these variants is predicted to result in lack of protein. Like the other fibrillar collagens, alpha2(V) has a long uninterrupted triple helix of Gly-X-Y repeats. The glycine residues have been shown to be important to the triple helix structure (Long et al, 1993, PMID 8218237; Bella et al, 1994, PMID 7695699; Shoulders and Raines, 2009, PMID 19344236). Ten of the variants curated here cause in frame deletion of 18-36 amino acids in the helical domain, and one is an in frame insertion/deletion. With the exception of one frameshift in the 3’ end of the gene, all of the other variants curated involved missense substitutions of a glycine residue in the helical domain. Alteration or loss of the Gly-X-Y repeats in the helical region is expected to result in a dominant-negative mechanism of disease, with up to 50% of Collagen V chains incorporating an altered alpha2(V) chain. The relationship between COL5A2 and classic EDS is also supported by experimental evidence. This includes the biochemical function of COL5A2 in regulating collagen fiber size in the extra-cellular matrix, which is consistent with the clinical features of the condition (Andrikopoulos et al., 1995, PMID: 7704020; Fichard et al, 1995, PMID: 8535602; the interaction of the gene product of COL5A2 (alpha2(V)) in a triple helical structure with the gene product of COL5A1 (alpha1(V), another gene with a definitive relationship with classic EDS (Bentz H, et al., 1978, PMID: 738278); functional alteration evidence in which fibroblasts and dermis samples from a patient with classic EDS and a COL5A2 variant show abnormalities in collagen solubility and collagen fibril size (Michalickova et al, 1998, PMID: 9425231); the clinical features of animal models including a cow model with skin abnormalities and a COL5A2 variant (Jacinto et al, 2020, PMID: 33143196), a conditional mouse knockout with fragile skin and poor wound-healing (Park et al, 2017, PMID: 28734943), and mouse model with an in frame deletion of the N-telopeptide domain in which homozygotes have fragile, hyperextensible skin (Andrikopoulos et al, 1995, PMID: 7704020). In summary, COL5A2 is definitively associated with autosomal dominant classic EDS. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease classification was approved by the General Gene Curation Expert panel on March 24th, 2021.