ClinVar

Description

Variant summary: CYP17A1 c.1039C>T (p.Arg347Cys) results in a non-conservative amino acid change located in the redox partner interaction domain (van den Akker_2002) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251414 control chromosomes. c.1039C>T has been reported in the literature as a compound heterozygous genotype in individuals with isolated 17,20-lyase deficiency presenting as Androgen insensitivity syndrome (AIS) (e.g., van den Akker_2002, ten Kate-Booij_2004) and in at least one homozygous individual affected with 17-Hydroxylase/17,20-lyase deficiency (e.g. Yamagata_2022). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1040G>A, p.Arg347His), supporting the critical relevance of codon 347 to CYP17A1 protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <1% of normal 17,20-Lyase activity and 13.6% of normal 17-alpha hydroxylase activity when expressed in COS-1 cells (van den Akker_2002). The following publications have been ascertained in the context of this evaluation (PMID: 12466376, 14747197, 34483146). ClinVar contains an entry for this variant (Variation ID: 1794). Based on the evidence outlined above, the variant was classified as pathogenic.