Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000087567 | SCV001589397 | pathogenic | Ehlers-Danlos syndrome, type 4 | 2020-09-10 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with arginine at codon 444 of the COL3A1 protein (p.Gly444Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with vascular Ehlers-Danlos syndrome (PMID: 10706896, 20518783). ClinVar contains an entry for this variant (Variation ID: 101329). 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. |
Collagen Diagnostic Laboratory, |
RCV000087567 | SCV000120457 | pathogenic | Ehlers-Danlos syndrome, type 4 | no assertion criteria provided | clinical testing |