ClinVar

Description

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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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: 10094548, Invitae). ClinVar contains an entry for this variant (Variation ID: 24440). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 579 of the COL4A5 protein (p.Gly579Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine.