ClinVar

Description

Variant summary: COL4A5 c.4228C>T (p.Arg1410Cys) results in a non-conservative amino acid change located in the triple-helical region of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.8e-05 in 182632 control chromosomes in the gnomAD database, including 5 hemizygotes, providing evidence supporting a benign role. c.4228C>T has been reported in the literature in at least one male individual and as a heterozygous genotype in one female individual affected with Alport Syndrome 1, X-Linked Recessive, and in both cases, the variant was reported to segregate with the disease phenotype, however no additional information (i.e. pedigrees, number and/or genotype of affected or unaffected family members) was provided. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9452056, 35580552, 8651296). Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as either VUS (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.