ClinVar Genomic variation as it relates to human health

The missense c.1226G>A p.Gly409Asp variant in COL4A5 gene has been reported in multiple individuals affected with Alport syndrome Yeo J et al. 2020; Gillion V et al. 2018; Mansilla MA et al. 2021. It has also been observed to segregate with disease in related individuals. The p.Gly409Asp variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic multiple submiters. The amino acid change p.Gly409Asp in COL4A5 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 409 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.

PM1_strong,PM2_p,PM5_strong,PP3_strong

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. ClinVar contains an entry for this variant (Variation ID: 24386). This missense change has been observed in individual(s) with Alport syndrome (PMID: 8651296, 25572247). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 409 of the COL4A5 protein (p.Gly409Asp).

The COL4A5 c.1226G>A variant is predicted to result in the amino acid substitution p.Gly409Asp. This variant was reported in an individual with Alport syndrome (Renieri et al 1996. PubMed ID: 8651296). This variant was also reported to segregate in a large family in individuals with features of COL4A5-related disorders (Zholdybayeva EV et al 2014. PubMed ID: 25572247). The p.Gly409 residue resides in the triple-helical region (residues 42 – 1456) of the COL4A5 protein (uniprot.org). The majority of pathogenic variants in COL4A5 substitute a glycine residue to a bulkier amino acid in the triple-helical domain (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

This patient is heterozygous for a known pathogenic variant, c.1226G>A (p.Gly409Asp), in exon 20 of the COL4A5 gene. This variant results in substitution of one of the invariant glycine residues in the triple helical domain of type IV collagen and is considered to be pathogenic. This variant has been reported as pathogenic in the COL4A5 Alport database (http://www.arup.utah.edu/database/ALPORT/ALPORT_display.php).