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). 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 Alport syndrome (PMID: 22921432, 33532864, 10094548). ClinVar contains an entry for this variant (Variation ID: 24666). This variant is also known as c.3861G>A. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 1220 of the COL4A5 protein (p.Gly1220Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid.