ClinVar Genomic variation as it relates to human health

Identified in at least one individual with clinical features of vascular Ehlers-Danlos syndrome (vEDS) (Pepin et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); Occurs in the triple helical domain and replaces the glycine in the canonical Gly-X-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(G295S); This variant is associated with the following publications: (PMID: 10706896, 9036918, 24922459)

The p.Gly462Ser variant (previously known as p.Gly295Ser) in COL3A1 has been reported in at least 1 individual with clinical features of Ehlers-Danlos syndrome type IV (EDS IV, vascular type (vEDS); Pepin 2014 PMID 24922459) and was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. Variants in COL3A1 affecting conserved glycine (Gly) residues of the G-X-Y repeat region in the triple helical collagen domain, where this variant is located, are strongly associated with EDS IV (Pepin 2000 PMID 10706896, Pepin 2014 PMID 24922459, Frank 2015 PMID: 25758994). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant EDS IV. ACMG/AMP Criteria applied: PS4_Supporting, PM2, PP3, PM1.

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the triple helix domain of COL3A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL3A1, variants that affect these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL3A1 protein function. ClinVar contains an entry for this variant (Variation ID: 101365). This missense change has been observed in individual(s) with clinical features of vascular Ehlers-Danlos syndrome (PMID: 24922459). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 462 of the COL3A1 protein (p.Gly462Ser).