CYP17A1

protein-coding

cytochrome P450 family 17 subfamily A member 1, the group of Cytochrome P450 family 17

Gene summary

This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum. It has both 17alpha-hydroxylase and 17,20-lyase activities and is a key enzyme in the steroidogenic pathway that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens. Mutations in this gene are associated with isolated steroid-17 alpha-hydroxylase deficiency, 17-alpha-hydroxylase/17,20-lyase deficiency, pseudohermaphroditism, and adrenal hyperplasia. [provided by RefSeq, Jul 2008]

Previous symbols:

CYP17

MANE transcript

NM_000102.4

Inheritance

ClinVar variants

P:154U:102B:211

Top phenotype

Adrenal hyperplasia, congenital, due to 17-alpha-hydroxylase deficiency

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr10:102,830,531-102,837,472

External References & Databases

Ensembl (ENSG00000148795)

Transcript & Mutation Effects

hg38 • Region Span ~6.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

46,XY disorder of sex development due to isolated 17,20-lyase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019597

Submitter: Orphanet

congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008730

Submitter: Orphanet

congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008730

Submitter: Natera

congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008730

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Adrenal hyperplasia, congenital, due to 17-alpha-hydroxylase deficiencyAR

Manifestation: Endocrine;Genitourinary; Oncologic

Intervention: Endocrine; Genitourinary; Oncologic

Rationale: Individuals may not necessarily manifest with adrenal crisis, but mineralocorticoid excess may result in severe hypokalaemic hypertension, and awareness may allow preventive measures and treatment (eg, including glucocorticoids and mineralcorticoid antagonists); Treatment of genitourinary anomalies, as well as related hypogonadotrophic hypogonadism (eg, with hormone replacement therapy, as well as surgery in some individuals), can be beneficial; Due to risk of malignancy, gonadectomy may be indicated in genotypic males

Refs: 4288776; 6039879; 4303304; 5456802; 999330; 6976525; 2843762; 2026124; 1648117; 2808364; 7629254; 8855840; 9360545; 9326943; 9177409; 11549685; 14671162; 16121340; 18559916; 20170344; 21823532; 22452398; 21550081; 22954317

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CYP17A1 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 443

Deficiency of steroid 17-alpha-monooxygenaseTotal: 173

Inborn genetic diseasesTotal: 39

Congenital adrenal hyperplasiaTotal: 21

CYP17A1-related disorderTotal: 19

17-alpha-hydroxylase/17,20-lyase deficiency, combined completeTotal: 19

not specifiedTotal: 16

17-alpha-hydroxylase/17,20-lyase deficiency, combined partialTotal: 10

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000102.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	1 clinvar	1 clinvar	6 clinvar	201 clinvar		209
missense	23 clinvar	37 clinvar	92 clinvar	10 clinvar		162
nonsense	20 clinvar	8 clinvar	1 clinvar			29
start loss		3 clinvar				3
frameshift	25 clinvar	20 clinvar				45
splice donor/acceptor (+/-2bp)	9 clinvar	7 clinvar	3 clinvar			19
Total	78	76	102	211	0	467

Highest pathogenic variant AF is 0.00007289792

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 54 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000102.4	RefSeq	NP_000093.1	8	MANE Select
ENST00000369887.4	Ensembl	ENSP00000358903.3	8	MANE Select
ENST00000638190.1	Ensembl	ENSP00000492539.1	6	Standard
ENST00000638190.2	Ensembl	ENSP00000492539.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cortisol synthesis and secretion - Homo sapiens (human)
Cushing,s syndrome - Homo sapiens (human)
Steroid hormone biosynthesis - Homo sapiens (human)
Prolactin signaling pathway - Homo sapiens (human)
Ovarian steroidogenesis - Homo sapiens (human)

Biological Process

steroid biosynthetic process
androgen biosynthetic process
glucocorticoid biosynthetic process
sex differentiation
steroid metabolic process

Molecular Function

steroid 17-alpha-monooxygenase activity
iron ion binding
oxygen binding
heme binding
17-alpha-hydroxyprogesterone aldolase activity

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
axon
neuronal cell body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000369887
Coding exons: 8
Length: 7003
Individuals with no LoFs: 125709
Homozygous LoFs: 0
Heterozygous LoFs: 39
Defined: 125748
p: 0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.24	219	277	0.791	0.0000162	3337
Missense (PolyPhen)		80	107.32	0.74545		1292
Synonymous	-0.0109	114	114	1.00	0.00000701	1002
Loss of Function	2.16	9	19.2	0.468	9.92e-7	226

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.00011	0.000099	rare
East Asian	0.00054	0.00054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00014	0.00014	rare
South Asian	0.00023	0.00023	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Conversion of pregnenolone and progesterone to their 17- alpha-hydroxylated products and subsequently to dehydroepiandrosterone (DHEA) and androstenedione. Catalyzes both the 17-alpha-hydroxylation and the 17,20-lyase reaction. Involved in sexual development during fetal life and at puberty. {ECO:0000269|PubMed:22266943}.;
Disease: DISEASE: Adrenal hyperplasia 5 (AH5) [MIM:202110]: A form of congenital adrenal hyperplasia, a common recessive disease due to defective synthesis of cortisol. Congenital adrenal hyperplasia is characterized by androgen excess leading to ambiguous genitalia in affected females, rapid somatic growth during childhood in both sexes with premature closure of the epiphyses and short adult stature. Four clinical types: 'salt wasting' (SW, the most severe type), 'simple virilizing' (SV, less severely affected patients), with normal aldosterone biosynthesis, 'non-classic form' or late- onset (NC or LOAH) and 'cryptic' (asymptomatic). {ECO:0000269|PubMed:10720067, ECO:0000269|PubMed:11549685, ECO:0000269|PubMed:11836339, ECO:0000269|PubMed:12466376, ECO:0000269|PubMed:14671162, ECO:0000269|PubMed:1515452, ECO:0000269|PubMed:1714904, ECO:0000269|PubMed:1740503, ECO:0000269|PubMed:19793597, ECO:0000269|PubMed:24140098, ECO:0000269|PubMed:24498484, ECO:0000269|PubMed:25650406, ECO:0000269|PubMed:2808364, ECO:0000269|PubMed:8027220, ECO:0000269|PubMed:8245018, ECO:0000269|PubMed:8345056, ECO:0000269|PubMed:8396144, ECO:0000269|PubMed:8550762, ECO:0000269|Ref.20}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.806

Intolerance Scores

LoFtool: 0.455
RVIS EVS: -0.69
RVIS percentile EVS: 14.97

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.897

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium