Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Molecular Medicine Center, |
RCV000785979 | SCV000920797 | pathogenic | Alport syndrome | 2019-06-11 | criteria provided, single submitter | clinical testing | Identified in all affected individuals, both male and female, in a large pedigree. |
Invitae | RCV001869174 | SCV002247687 | likely pathogenic | not provided | 2021-01-11 | criteria provided, single submitter | clinical testing | 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. 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. 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). This variant has been observed in individual(s) with clinical features of Alport syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 635111). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 383 of the COL4A5 protein (p.Gly383Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. |