Submissions for variant NM_000102.4(CYP17A1):c.1117C>T (p.His373Tyr)

dbSNP: rs1423560123

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001376807	SCV001573978	pathogenic	not provided	2023-03-04	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 373 of the CYP17A1 protein (p.His373Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with 17alpha-hydroxylase/17,20-lyase-deficiency (PMID: 29278670). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1065950). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYP17A1 protein function. Experimental studies have shown that this missense change affects CYP17A1 function (PMID: 29278670). This variant disrupts the p.His373 amino acid residue in CYP17A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8245018, 10877510, 11549876, 12706306, 24140098). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004699349	SCV005205139	pathogenic	Congenital adrenal hyperplasia	2024-06-17	criteria provided, single submitter	clinical testing	Variant summary: CYP17A1 c.1117C>T (p.His373Tyr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251058 control chromosomes. c.1117C>T has been reported in the literature in at least one compound heterozygous individual affected with congential adrenal hyperplasia due to 17-alpha-hydroxylase/17,20-lyase deficiency (e.g., Sun_2017). A different variant affecting the same codon has been classified as pathogenic by our lab (c.1117C>A, p.His373Asn), supporting the critical relevance of codon 373 to CYP17A1 protein function. At least one publication reports experimental evidence evaluating an impact on protein function; studies of transfected HEK293 cells demonstrated that the variant completely abolished 17-hydroxylase activity of CYP17A1. The following publication has been ascertained in the context of this evaluation (PMID: 29278670). ClinVar contains an entry for this variant (Variation ID: 1065950). Based on the evidence outlined above, the variant was classified as pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001826120	SCV005418375	likely pathogenic	Deficiency of steroid 17-alpha-monooxygenase		criteria provided, single submitter	clinical testing	PP3+PM2_Supporting+PM3+PM5
Natera, Inc.	RCV001826120	SCV002091791	likely pathogenic	Deficiency of steroid 17-alpha-monooxygenase	2020-04-03	no assertion criteria provided	clinical testing