ClinVar Genomic variation as it relates to human health

Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A5 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (HGMD; Jais et al., 2000); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15044104, 19919694, 29526710, 32405592, 9848783, 29127259, 15780079, 15347445, 33040356)

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1030 of the COL4A5 protein (p.Gly1030Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Alport syndrome (PMID: 9848783, 24130771). ClinVar contains an entry for this variant (Variation ID: 24591). 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 with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic.

COL4A5: PM1:Strong, PM2, PS4:Moderate, PP3, PP4

The COL4A5 c.3088G>A (p.Gly1030Ser) variant is a missense variant that has been reported in a hemizygous state in three male individuals and in a heterozygous state in one female individual with Alport syndrome (Martin et al. 1998; Wang et al. 2004; Liu et al. 2017; Kamura et al. 2020). All the affected individuals presented with hematuria, with two individuals also presenting with sensorineural hearing loss. The p.Gly1030Ser variant segregated in one family in which it was present in the affected father and son (Kamura et al. 2020). This variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so is presumed to be rare. Glycine substitutions in missense variants in the collagenous domain are the most common variant type found in X-linked Alport syndrome (Kamura et al. 2020). Circular dichroism spectroscopy studies showed that the p.Gly1030Ser variant affected secondary structure of the protein and results in less beta-sheet and more random coil structure compared to wild type (Wang et al. 2004). In addition, expression of the p.Gly1030Ser variant in HEK293T cells showed a significant reduction of over 50% in extracellular secretion of COL4A5 compared to wild type (Kamura et al. 2020). Based on the collective evidence, the p.Gly1030Ser variant is classified as likely pathogenic for Alport syndrome.