Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001964118 | SCV002252524 | likely pathogenic | not provided | 2021-01-10 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals with COL4A5-related conditions. This sequence change replaces glycine with alanine at codon 1229 of the COL4A5 protein (p.Gly1229Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). 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 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). 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. |
| Institute of Medical Genetics and Applied Genomics, |
RCV005401886 | SCV006059922 | likely pathogenic | X-linked Alport syndrome | 2025-04-29 | criteria provided, single submitter | clinical testing |