ClinVar

Description

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant negative is a mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive (Alport syndrome) and dominant (Alport syndrome and benign familial hematuria) disease (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine (exon 28). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 (31 heterozygotes, 0 homozygotes). (P) 0600 - Variant is located in an annotated motif (G-X-Y repeat in a triple helix motif; NCBI, PDB). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0702 - Comparable variants have strong previous evidence for pathogenicity. Multiple substitutions of glycine in the G-X-Y motif within the collagen triple helix domain have been reported pathogenic (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously described as pathogenic and segregated with disease in families with either thin basement membrane nephropathy (TBMN) or autosomal recessive Alport syndrome (ARAS) (ClinVar; PMID: 30476138; PMID: 14871398; PMID: 29854973; PMID: 24130771; PMID: 24052634; PMID: 25229338; PMID: 23325022; PMID: 29098738). (P) 1206 - Variant is paternally inherited. However, it is suggested that carriers may present with milder symptoms (PMID: 30450445), which can potentially be difficult to diagnose (PMID: 28704582). (N)