Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001949422 | SCV002239070 | pathogenic | not provided | 2021-02-01 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Gly1261 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been observed in individuals with COL4A5-related conditions (PMID: 28356090), which suggests that this may be a clinically significant amino acid residue. 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. This variant has been observed in individual(s) with clinical features of Alport syndrome (PMID: 9848783, Invitae). ClinVar contains an entry for this variant (Variation ID: 24682). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 1261 of the COL4A5 protein (p.Gly1261Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. |