rs760695410 — CYP17A1 p.His373Leu

Pathogenic missense variant in CYP17A1 disrupting the heme-binding region of the enzyme, abolishing both 17α-hydroxylase and 17,20-lyase activity; the most common CYP17A1 mutation in East Asian populations (Chinese, Japanese, Korean); homozygotes develop combined 17α-hydroxylase/17,20-lyase deficiency with cortisol deficiency, sex steroid absence, and mineralocorticoid excess causing hypertension

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CYP17A1 p.His373Leu — The East Asian Founder Mutation That Silences Steroid Biosynthesis

CYP17A111 CYP17A1
Cytochrome P450 17α-hydroxylase/17,20-lyase — a bifunctional enzyme at the central branch point of the steroid hormone biosynthesis pathway. Without it, neither cortisol nor sex steroids can be made from cholesterol precursors encodes the single enzyme responsible for two consecutive reactions that are essential for all downstream steroid hormone production. The rs760695410 variant (c.1118A>T, p.His373Leu) is a missense change that destroys CYP17A1 function and, in homozygous individuals, causes combined 17α-hydroxylase/17,20-lyase deficiency (17OHD) — a rare form of congenital adrenal hyperplasia (CAH) defined by a paradoxical clinical triad: hypertension from mineralocorticoid excess, sex steroid deficiency causing absent pubertal development, and cortisol insufficiency creating adrenal crisis risk.

Among all known CYP17A1 pathogenic variants, p.His373Leu stands out for its population specificity. Multiple independent case series from China, Japan, and Korea have identified this mutation as the most prevalent CYP17A1 variant in East Asian 17OHD patients — a pattern consistent with a founder effect22 founder effect
When a mutation traces back to a single ancestral individual in a population, it can reach a higher-than-expected frequency in that population's descendants. In the global context of >100 CYP17A1 mutations, p.His373Leu is the dominant allele causing 17OHD throughout Northeast Asia.

The Mechanism

CYP17A1 catalyzes two reactions: 17α-hydroxylation33 17α-hydroxylation
The first step — adding a hydroxyl group at the C17 position of pregnenolone or progesterone to create 17α-hydroxypregnenolone and 17α-hydroxyprogesterone, which are essential precursors for cortisol and 17,20-lyase activity44 17,20-lyase activity
The second step — cleaving the C17–C20 bond to convert 17α-hydroxypregnenolone into DHEA and 17α-hydroxyprogesterone into androstenedione, entering the sex steroid biosynthesis pathway.

Histidine 373 sits within a region critical for heme incorporation. All cytochrome P450 enzymes require a heme cofactor — an iron-containing porphyrin ring — to carry out oxidative catalysis. Functional studies demonstrated that the p.His373Leu mutant fails to incorporate the heme prosthetic group55 Functional studies demonstrated that the p.His373Leu mutant fails to incorporate the heme prosthetic group
Kim et al. 2018 (PMID 30229581) expressed His373Leu in HEK293T cells and measured 17α-hydroxylase activity at 21.9 nmol/L, compared to 744 nmol/L for wild-type — a 97% reduction. Neither the His373Leu mutant nor a companion frameshift mutant formed a heme-binding structure. Leucine, unlike histidine, lacks the imidazole side chain that coordinates to the heme iron, and although His373 is not the direct iron ligand (that role belongs to the conserved axial cysteine at position 442), its distance from the heme in three-dimensional space suggests the substitution causes global structural disruption that secondarily prevents heme incorporation.

When CYP17A1 is non-functional, steroidogenesis in the adrenal cortex and gonads is blocked at pregnenolone. The substrate pool cannot proceed toward cortisol or sex steroids; instead, it flows into the mineralocorticoid branch, accumulating 11-deoxycorticosterone (DOC) and corticosterone. These potent mineralocorticoids cause sodium retention, hypertension, and hypokalemia. Chronically elevated ACTH (which rises because there is no cortisol to suppress it) drives adrenal hyperplasia and amplifies this mineralocorticoid excess.

The Evidence

The His373Leu mutation was first reported in Chinese families with 17OHD. Qiao et al. 200366 Qiao et al. 2003
A complex heterozygous mutation of His373Leu and Asp487–Ser488–Phe489 deletion in human cytochrome P450c17 causes 17α-hydroxylase/17,20-lyase deficiency in three Chinese sisters. Mol Cell Endocrinol 201:189–195 identified compound heterozygosity for p.His373Leu (paternal allele) and a deletion in exon 8 (maternal allele) in three siblings presenting with primary amenorrhea and hypertension. All three sisters shared the same compound heterozygous genotype — family evidence for the variant's stability and pathogenicity.

Park et al. 201277 Park et al. 2012
Homozygous CYP17A1 mutation (H373L) identified in a 46,XX female with combined 17α-hydroxylase/17,20-lyase deficiency. Gynecol Endocrinol 28:545–548 reported the first documented homozygous H373L case in Korea — a 23-year-old woman presenting with absent spontaneous puberty and hypertension, with markedly elevated progesterone and 11-deoxycorticosterone and suppressed sex steroids, confirming complete dual enzyme loss.

The East Asian founder effect was catalogued by Kim et al. 201488 Kim et al. 2014
A review of the literature on common CYP17A1 mutations in adults with 17-hydroxylase/17,20-lyase deficiency, a case series of such mutations among Koreans. Metabolism 63:42–49. Among six Korean 17OHD patients in their series (three 46,XX, three 46,XY), p.H373L was the most common variant — consistent with reports from China and Japan — providing robust evidence for a shared ancestral founder mutation across Northeast Asian populations.

Quantitative functional analysis was provided by Kim et al. 201899 Kim et al. 2018
Functional identification of compound heterozygous mutations in CYP17A1. Endocrinol Metab 33:387–392, confirming the near-complete loss of both enzymatic activities. The largest global summary comes from Willemsen et al. 20251010 Willemsen et al. 2025
Meta-analysis of 465 patients across 178 studies, JCEM 110:e1261: hypertension was documented in 57% of 17OHD patients, hypokalemia in 45%, and primary amenorrhea in 38% of females. Severe complete-loss variants like p.His373Leu are associated with hypocortisolism and complete sexual infantilism, while partial-activity mutations produce milder phenotypes.

Practical Actions

For homozygous individuals (AA genotype), this is a managed medical condition requiring specialist endocrine care. Glucocorticoid replacement (hydrocortisone) suppresses ACTH, halts DOC excess, and normalizes blood pressure and potassium — the hypertension in 17OHD is mineralocorticoid-driven and resolves with adequate ACTH suppression, not with conventional antihypertensives. Sex hormone replacement induces and maintains secondary sexual characteristics appropriate to the patient's chromosomal sex and gender identity. Bone density monitoring is warranted because sex steroid deficiency during adolescence impairs bone mineralization.

For heterozygous carriers (AT genotype), no clinical manifestation is expected — one functional gene copy provides adequate steroidogenesis. The clinical relevance is reproductive: if a carrier's partner also carries any CYP17A1 loss-of-function allele, each pregnancy carries a 25% chance of an affected child.

Interactions

Compound heterozygosity between p.His373Leu and any second CYP17A1 loss-of-function allele produces the same complete-deficiency phenotype as homozygosity, since both CYP17A1 copies are non-functional. In case series, common compound-heterozygous combinations include p.His373Leu with the p.Tyr329Kfs frameshift (rs28933378, the most prevalent CYP17A1 allele globally) or with the p.Asp487_Phe489del deletion.

Because CYP17A1 operates at the branch point between mineralocorticoid and sex steroid synthesis, complete loss creates a steroidogenesis network effect: upstream substrates (pregnenolone, progesterone) accumulate while all downstream products — DHEA, androstenedione, testosterone, estradiol — are absent. Both the adrenal gland and gonads are affected, since CYP17A1 is expressed in both tissues.

Genotype Interpretations

What each possible genotype means for this variant.

TT Non-Carrier Normal

Common genotype — no CYP17A1 p.His373Leu variant detected

You have two copies of the common T allele (plus-strand) at rs760695410. The A allele corresponding to the pathogenic p.His373Leu change is not present in your genome. This genotype is the vast majority globally — the disease-causing allele is extremely rare outside East Asian populations and even within East Asian populations occurs at only a fraction of a percent of chromosomes. Your CYP17A1 enzyme carries histidine at position 373, supporting normal heme incorporation and full 17α-hydroxylase and 17,20-lyase activity.

AT Heterozygous Carrier Carrier

One copy of the p.His373Leu variant — carrier of a CYP17A1 pathogenic allele

17α-hydroxylase/17,20-lyase deficiency (17OHD) is an autosomal recessive condition — both copies of CYP17A1 must carry loss-of-function variants for the disorder to manifest. Heterozygous carriers in published case series have been uniformly asymptomatic, with normal steroid profiles under basal conditions. However, ACTH stimulation testing has demonstrated measurable but subclinical reductions in 17α-hydroxylase reserve in heterozygous carriers of severe CYP17A1 alleles, as shown for other null alleles in the gene (Qiao et al. 2010, PMID 19508587).

The p.His373Leu allele is the dominant CYP17A1 disease allele in populations of Chinese, Japanese, and Korean descent. For individuals from these populations, the prior probability that a reproductive partner carries a second CYP17A1 allele is higher than in other ancestries, making carrier testing in partners more clinically informative.

Affected children with complete 17OHD present in infancy or childhood with primary amenorrhea (or ambiguous genitalia in 46,XY), hypertension, and hypokalemia. Early diagnosis and treatment — glucocorticoid replacement plus sex hormone replacement — allows full developmental and reproductive outcomes when begun before the expected age of puberty.

AA Homozygous — 17α-Hydroxylase/17,20-Lyase Deficiency Homozygous

Two copies of p.His373Leu — combined 17α-hydroxylase/17,20-lyase deficiency requiring specialist management

The clinical presentation of homozygous His373Leu-mediated 17OHD follows from the complete loss of both CYP17A1 enzymatic activities:

Mineralocorticoid excess: With no 17α-hydroxylase to divert pregnenolone toward cortisol, adrenal steroidogenesis flows entirely into the DOC and corticosterone branch. DOC is a potent mineralocorticoid — it retains sodium, expands plasma volume, suppresses renin and aldosterone, and causes hypertension. Hypokalemia follows. This is not essential hypertension; it resolves with glucocorticoid replacement, which suppresses ACTH and halts DOC overproduction.

Cortisol deficiency: Absent cortisol removes the negative feedback to the hypothalamic-pituitary axis, causing chronically elevated ACTH, which in turn drives bilateral adrenal hyperplasia. Adrenal crisis — life-threatening hypotension, hypoglycemia, and electrolyte catastrophe — can occur under physiological stress (illness, surgery, trauma) and is the most immediate medical risk.

Sex steroid deficiency: CYP17A1 is the only route from pregnenolone to DHEA and androstenedione. Without it, neither adrenal nor gonadal sex steroids can be made. In 46,XX individuals: external female phenotype (CYP17A1 is not required for female gonadal development at the fetal stage), but absent puberty — no breast development, no pubic or axillary hair, primary amenorrhea, infantile uterus. In 46,XY individuals: absent fetal testosterone from the testes means incomplete masculinization — patients typically present with external female phenotype, a blind-ending vagina, no uterus, and undescended testes.

The Korean case by Park et al. 2012 (PMID 22452398) directly documents this phenotype in a homozygous H373L individual: a 23-year-old presenting with absent spontaneous puberty, hypertension, markedly elevated progesterone and 11-deoxycorticosterone, and suppressed sex steroids. The Willemsen 2025 meta-analysis (PMID 39500362) confirms that complete loss-of-function alleles are associated with hypocortisolism and complete sexual infantilism across the global 17OHD case literature.

Treatment is effective. Glucocorticoid replacement (hydrocortisone) and sex hormone replacement, initiated at or before the expected age of puberty, allows normal development and — in females — fertility with assisted reproduction.