Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV001993916 | SCV002248841 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2021-12-15 | criteria provided, single submitter | clinical testing | 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. This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 294 of the COL3A1 protein (p.Gly294Arg). |
All of Us Research Program, |
RCV001993916 | SCV005427268 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2024-09-02 | criteria provided, single submitter | clinical testing | The c.880G>A (p.Gly294Arg) variant in COL3A1 gene affects a conserved glycine residue. Changes to glycine in COL3A1 protein are significantly enriched in individuals with COL3A1-related conditions (PMID: 24922459, 25758994). Glycine residues within the Gly-X-Y repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). This variant has not been reported in individuals affected with Ehlers-Danlos syndrome or other COL3A1 related phenotypes. In-silico computational prediction tools suggest that the p.Gly294Arg variant may have deleterious effect on the protein function (REVEL score: 0.989). This variant is absent in the general population database gnomAD (v2.1.1). Therefore, the c.880G>A (p.Gly294Arg) variant in COL3A1 is classified as likely pathogenic. |