Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001377183 | SCV001574442 | pathogenic | Ehlers-Danlos syndrome, type 4 | 2023-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 633 of the COL3A1 protein (p.Gly633Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Ehlers-Danlos syndrome, vascular type (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 549890). 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 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). For these reasons, this variant has been classified as Pathogenic. |
| Center of Vascular Surgery, |
RCV000664467 | SCV000778841 | risk factor | Congenital aneurysm of ascending aorta | no assertion criteria provided | clinical testing |