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 (Stenson et al., 2014; Jais et al., 2000); Not observed in large population cohorts (Lek et al., 2016); 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: 15954103, 21505094, 30647093)

PP2, PP3, PM1, PM2_supporting, PS4_moderate

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 426 of the COL4A5 protein (p.Gly426Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Alport syndrome (PMID: 15954103, 21505094, 30647093; Invitae). ClinVar contains an entry for this variant (Variation ID: 24393). 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.

The c.1276G>A (p.G426R) alteration is located in exon 20 (coding exon 20) of the COL4A5 gene. This alteration results from a G to A substitution at nucleotide position 1276, causing the glycine (G) at amino acid position 426 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in multiple individuals with clinical features of COL4A5-related Alport syndrome (Zhou, 2023; Shulman, 2021; Groopman, 2019; Yao, 2019; Ma, 2011; Nagel, 2005). This amino acid position is highly conserved in available vertebrate species. In an assay testing COL4A5 function, this variant showed a functionally abnormal result (Omachi, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

This variant (GRCh38; NM_033380.3:c.1276G>A:p.Gly426Arg) results in a missense mutation with the conversion of Glycine (Polar amino acid) to Arginine (Basic amino acid) in the COL4A5 protein. Located in a mutational hot spot and/or critical and well established functional domain without benign variation. Not observed at significant frequency in large population cohorts (gnomAD). This variant has a strong Conservation score. Multiple lines of computational evidence support a deleterious effect on the gene or gene product for this variant. ClinVar contains an entry for this variant (Variation ID: 24393). This variant is associated with the following publications: PubMed: 21505094, 15954103, 23720012, 29526710, 30586318, 27627812 In summary, this variant meets our criteria for classification as pathogenic based on the evidence outlined.

The COL4A5 c.1276G>A variant is predicted to result in the amino acid substitution p.Gly426Arg. The p.Gly426Arg residue resides in the triple-helical domain (residues 42 – 1456; uniprot.org) of the COL4A5 protein where substitutions of the glycine (Gly) residue are usually expected to be pathogenic (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). This variant has been reported in individuals with Alport syndrome and/or focal segmental glomerulosclerosis (see for example, Nagel et al. 2005. PubMed ID: 15954103; Supp. Table 7 in Groopman et al. 2018. PubMed ID: 30586318; Yao et al. 2019. PubMed ID: 30647093). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.