rs104894137 — CYP17A1 Pro342Thr

CYP17A1 Pro342Thr — Partial 17α-Hydroxylase/17,20-Lyase Deficiency

CYP17A1¹¹ CYP17A1
cytochrome P450 17α-hydroxylase/17,20-lyase — the enzyme that performs two sequential reactions in steroid hormone synthesis: first converting pregnenolone and progesterone to their 17-hydroxy forms, then cleaving the two-carbon side chain to produce DHEA and androstenedione sits at the branch point between the mineralocorticoid and sex steroid pathways. When CYP17A1 works normally, the adrenal glands and gonads can produce cortisol and sex hormones. When it is impaired, the steroid synthesis pipeline is diverted: mineralocorticoid precursors accumulate (causing hypertension and low potassium), while sex steroids — testosterone in males, estrogens in females — cannot be made in adequate quantities. The rs104894137 Pro342Thr variant is a rare missense mutation that reduces CYP17A1 enzyme activity to roughly 40–45% of normal. This partial impairment produces a milder clinical picture than complete deficiency, but the consequences for steroidogenesis, blood pressure, and reproductive capacity are real and actionable.

The Mechanism

The p.Pro342Thr substitution²² p.Pro342Thr substitution
a C-to-A transversion in exon 6 of CYP17A1, c.1024C>A on the coding strand; gene is on the minus strand of chr10, so the plus-strand change is G>T at position 102,832,626 (GRCh38) replaces a rigid proline residue at position 342 — within the heme-binding and substrate-positioning region of the enzyme — with the more flexible threonine. The conformational consequence is partial disruption of the active site geometry without destroying the protein itself: expression of the Pro342Thr mutant in COS-1 cells produces a normal amount of immunodetectable P450-17α protein, but both the 17α-hydroxylase and 17,20-lyase enzymatic activities are reduced to 40–45% of those of the wild-type enzyme³³ expression of the Pro342Thr mutant in COS-1 cells produces a normal amount of immunodetectable P450-17α protein, but both the 17α-hydroxylase and 17,20-lyase enzymatic activities are reduced to 40–45% of those of the wild-type enzyme. This "partial loss of function" phenotype means cortisol synthesis is impaired but not abolished, mineralocorticoid precursors (11-deoxycorticosterone, corticosterone) accumulate in excess of what ACTH suppression can prevent at baseline, and sex steroid synthesis is reduced but may allow some secondary sexual development — particularly in females with partial 17-OHD, where residual ovarian estrogen output can be sufficient for some pubertal changes. The original clinical report establishing this variant found it in compound heterozygosity with a nonsense mutation (Arg239*) in a 46,XY male with ambiguous external genitalia, demonstrating that even 40–45% residual lyase activity is insufficient for complete male virilization.

The Evidence

The foundational study characterizing Pro342Thr was Ahlgren et al. 1992 in the Journal of Clinical Endocrinology & Metabolism⁴⁴ Ahlgren et al. 1992 in the Journal of Clinical Endocrinology & Metabolism
Compound heterozygous mutations (Arg 239→stop, Pro 342→Thr) in the CYP17 gene lead to ambiguous external genitalia in a male patient with partial combined 17α-hydroxylase/17,20-lyase deficiency. JCEM 74(3):667–672. The patient was a 46,XY individual with ambiguous genitalia who was compound heterozygous: one allele (maternal) carried the truncating Arg239* mutation, the other (paternal) carried Pro342Thr. Site-directed mutagenesis of the Pro342Thr allele into human CYP17 cDNA and expression in COS-1 cells demonstrated that this single amino acid change is sufficient to reduce both hydroxylase and lyase activities to 40–45% of normal, confirming it as the molecular cause of partial enzyme impairment. The study also established a functional threshold: greater than 20% of normal 17,20-lyase activity is required for complete male virilization, illustrating why partial deficiency produces ambiguous rather than female-typical genitalia in 46,XY.

ClinVar classifies rs104894137 as Pathogenic for 17-alpha-hydroxylase/17,20-lyase deficiency, combined partial (RCV000001856)⁵⁵ Pathogenic for 17-alpha-hydroxylase/17,20-lyase deficiency, combined partial (RCV000001856), with a second submission of Likely-Pathogenic. OMIM records this as allelic variant 609300.0007 in the CYP17A1 gene entry.

The clinical consequences of partial 17α-hydroxylase deficiency in 46,XX females were further characterized in a 2022 Frontiers in Endocrinology cohort of 8 patients⁶⁶ 2022 Frontiers in Endocrinology cohort of 8 patients: most presented with oligomenorrhea or primary amenorrhea as the sole symptom, with mildly elevated FSH, suppressed testosterone, and elevated progesterone. The condition is frequently under-diagnosed because cortisol deficiency may be mild and hypertension may be absent or modest in partial forms. A 2023 study of ART outcomes in five women with CYP17A1 deficiency⁷⁷ 2023 study of ART outcomes in five women with CYP17A1 deficiency found that persistently elevated progesterone during ovarian stimulation prevents endometrial receptivity, necessitating a freeze-all strategy; frozen embryo transfer after GnRH agonist plus dexamethasone suppression of progesterone achieved four live births.

Practical Actions

Homozygous carriers of Pro342Thr or compound heterozygotes combining Pro342Thr with a second loss-of-function CYP17A1 allele have a confirmed steroidogenic defect. The cornerstones of management are glucocorticoid replacement to suppress ACTH-driven mineralocorticoid excess (treating hypertension and hypokalemia), sex steroid replacement at puberty and throughout adulthood, and — for women who want to conceive — specialist-supervised IVF using protocols that suppress endogenous progesterone before embryo transfer. Heterozygous carriers have 50–75% residual enzyme activity (one normal allele + one Pro342Thr allele) and are not expected to have clinical 17-OHD, but their children are at risk if the partner also carries a CYP17A1 pathogenic variant.

Blood pressure, serum potassium, and a full adrenal steroid profile are the priority tests for individuals confirmed to carry biallelic CYP17A1 pathogenic variants. Even in partial deficiency, hypertension and hypokalemia may be mild or intermittent and are easily missed without systematic measurement.

Interactions

Rs104894136 (Arg239*) is the nonsense allele that was found on the complementary chromosome in the original 1992 compound heterozygous patient; together with Pro342Thr it produces partial rather than complete deficiency because Pro342Thr still allows ~40–45% residual CYP17A1 activity. Two complete loss-of-function alleles (e.g., Arg239* + Arg239*) produce the complete form of 17-OHD with more severe phenotype: sexual infantilism, severe hypertension, and marked hypokalemia. The partial vs. complete phenotype distinction thus depends on which CYP17A1 alleles are co-inherited.

The common regulatory polymorphism rs743572 (CYP17A1 5′-UTR T>C) is sometimes measured in the context of cancer and hormonal conditions, but is distinct from this coding deficiency allele and does not cause enzyme impairment.