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This study examined the molecular characteristics of Gly substitutions that determine the severity of clinical features. Pathogenic <jats:italic>COL4A5<\/jats:italic> variants affecting Gly in the Leiden Open Variation Database in males with X-linked Alport syndrome were correlated with age at kidney failure (n\u2009=\u2009157) and hearing loss diagnosis (n\u2009=\u200980). Heterozygous pathogenic <jats:italic>COL4A3<\/jats:italic> and <jats:italic>COL4A4<\/jats:italic> variants affecting Gly (n\u2009=\u2009304) in autosomal dominant Alport syndrome were correlated with the risk of haematuria in the UK 100,000 Genomes Project. Gly substitutions were stratified by exon location (1 to 20 or 21 to carboxyl terminus), being adjacent to a non-collagenous region (interruption or terminus), and the degree of instability caused by the replacement residue. Pathogenic <jats:italic>COL4A5<\/jats:italic> variants that resulted in a Gly substitution with a highly destabilising residue reduced the median age at kidney failure by 7\u00a0years (p\u2009=\u20090.002), and age at hearing loss diagnosis by 21\u00a0years (p\u2009=\u20090.004). Substitutions adjacent to a non-collagenous region delayed kidney failure by 19\u00a0years (p\u2009=\u20090.014). Heterozygous pathogenic <jats:italic>COL4A3<\/jats:italic> and <jats:italic>COL4A4<\/jats:italic> variants that resulted in a Gly substitution with a highly destabilising residue (Arg, Val, Glu, Asp, Trp) were associated with an increased risk of haematuria (p\u2009=\u20090.018), and those adjacent to a non-collagenous region were associated with a reduced risk (p\u2009=\u20090.046). Exon location had no effect. In addition,\u00a0<jats:italic>COL4A5<\/jats:italic> variants adjacent to non-collagenous regions were over-represented in the normal population in gnomAD (p\u2009&lt;\u20090.001). The nature of the substitution and of nearby residues determine the risk of haematuria, early onset kidney failure and hearing loss for Gly substitutions in X-linked and autosomal dominant Alport syndrome.<\/jats:p>","DOI":"10.1038\/s41598-022-06525-9","type":"journal-article","created":{"date-parts":[[2022,2,17]],"date-time":"2022-02-17T11:02:53Z","timestamp":1645095773000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Genotype\u2013phenotype correlations for COL4A3\u2013COL4A5 variants resulting in Gly substitutions in Alport syndrome"],"prefix":"10.1038","volume":"12","author":[{"given":"Joel T.","family":"Gibson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Shenelli Croos Dabrera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krushnam","family":"Shukla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hansj\u00f6rg","family":"Rothe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale","family":"Hilbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantinos","family":"Deltas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Storey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beata S.","family":"Lipska-Zi\u0119tkiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie M. 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