Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ce |
RCV001532703 | SCV001748374 | likely pathogenic | not provided | 2023-10-01 | criteria provided, single submitter | clinical testing | COL4A5: PM1:Strong, PM2, PM5, PS4:Supporting |
Invitae | RCV001532703 | SCV004299663 | pathogenic | not provided | 2023-05-23 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the triple helix domain of COL4A5. 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 COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) 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 COL4A5 protein function. ClinVar contains an entry for this variant (Variation ID: 587139). This missense change has been observed in individuals with Alport syndrome (PMID: 24033287, 29854973). This variant is present in population databases (rs767619131, gnomAD 0.001%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 138 of the COL4A5 protein (p.Gly138Ser). |