ClinVar Genomic variation as it relates to human health

A hemizygous missense variant, NM_000495.4(COL4A5):c.3685G>A, has been identified in exon 41 of 51 of the COL4A5 gene. The variant is predicted to result in an amino acid change from a glycine to a serine at position 1229 of the protein, NP_000486.1(COL4A5):p.(Gly1229Ser). The glycine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the collagen domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G). However, this variant has previously been described in three patients clinically diagnosed with Alport syndrome (Liu, J., et al. (2017), Wang, F., et al. (2012)). A different variant in the same codon resulting in a change to an aspartate, p.(Gly1229Asp) was found to segregate with disease within a family with Alport syndrome (Cheong, H., et al. (2000), while another variant with a change to a cysteine, p.(Gly1229Cys) was described in a male with Alport syndrome (Moriniere, V., et al. (2014)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.

The COL4A5 c.3685G>A variant is predicted to result in the amino acid substitution p.Gly1229Ser. This variant has been reported in several unrelated individuals with Alport syndrome (Supp. Table 2 in Jayasinghe K et al 2020. PubMed ID: 32939031; Liu JH et al 2017. PubMed ID: 28542346; Supp. Table 1 in Wang et al. 2012. PubMed ID: 22921432). The p.Gly1229 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 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. 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: 562403). This missense change has been observed in individuals with Alport syndrome (PMID: 28542346). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1229 of the COL4A5 protein (p.Gly1229Ser).