ClinVar

Description

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.