Submissions for variant NM_000102.4(CYP17A1):c.1040G>A (p.Arg347His)

gnomAD frequency: 0.00001  dbSNP: rs61754278

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001387555	SCV001588220	pathogenic	not provided	2024-02-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 347 of the CYP17A1 protein (p.Arg347His). This variant is present in population databases (rs61754278, gnomAD 0.007%). This missense change has been observed in individuals with isolated 17,20-lyase deficiency (PMID: 9326943, 12466376). ClinVar contains an entry for this variant (Variation ID: 1787). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CYP17A1 function (PMID: 9326943, 9601054, 12466376, 27426448). This variant disrupts the p.Arg347 amino acid residue in CYP17A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12466376). 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	RCV000185577	SCV002015115	pathogenic	Deficiency of steroid 17-alpha-monooxygenase	2021-10-29	criteria provided, single submitter	clinical testing	Variant summary: CYP17A1 c.1040G>A (p.Arg347His) results in a non-conservative amino acid change in 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 1.6e-05 in 251412 control chromosomes (gnomAD). c.1040G>A has been reported in the literature in multiple homozygous individuals affected with Isolated 17,20 Lyase Deficiency (Geller_1997, van den Akker_2002). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant confers minimal 17,20-lyase activity while it retains 17-alpha-hydroxylase function (e.g. Geller_1997, Geller_1999, van den Akker_2002, Peng_2016, Kim_2021). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000185577	SCV002810541	pathogenic	Deficiency of steroid 17-alpha-monooxygenase	2021-11-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000185577	SCV005059307	pathogenic	Deficiency of steroid 17-alpha-monooxygenase	2023-12-02	criteria provided, single submitter	clinical testing
OMIM	RCV000001860	SCV000022016	pathogenic	17,20-lyase deficiency, isolated	2002-12-01	no assertion criteria provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000185577	SCV000238477	pathogenic	Deficiency of steroid 17-alpha-monooxygenase	2015-06-10	no assertion criteria provided	research	The CYP17A1 variant (c.1040G>A; p.Arg347His) was identified in four patients (mostly homozygotes and one compound heterozygote) with ambiguous external genitalia and normal glucocorticoid levels. Multiple functional studies showed moderate to severe impaired lyase activity, with some residual activity preserving the 17-alpha hydroxylase function. This variant is considered a pathogenic variant.
Natera, Inc.	RCV000185577	SCV002086689	pathogenic	Deficiency of steroid 17-alpha-monooxygenase	2020-03-02	no assertion criteria provided	clinical testing