CYP11A1

protein-coding

cytochrome P450 family 11 subfamily A member 1, the group of Cytochrome P450 family 11

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 mitochondrial inner membrane and catalyzes the conversion of cholesterol to pregnenolone, the first and rate-limiting step in the synthesis of the steroid hormones. Two transcript variants encoding different isoforms have been found for this gene. The cellular location of the smaller isoform is unclear since it lacks the mitochondrial-targeting transit peptide. [provided by RefSeq, Jul 2008]

Previous symbols:

CYP11A

MANE transcript

NM_000781.3

Inheritance

AD, AR

ClinVar variants

P:69U:126B:151

Top phenotype

Adrenal insufficiency, congenital, with 46,XY sex reversal, partial or complete

gnomAD constraint

pLI —, LoF o/e 0.56

Max pathogenic AF

—

Genomic locus

chr15:74,337,759-74,367,646

External References & Databases

Ensembl (ENSG00000140459)

Transcript & Mutation Effects

hg38 • Region Span ~29.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiencySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013400

Submitter: Orphanet

Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013400

Submitter: Natera

Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013400

Submitter: Labcorp Genetics (formerly Invitae)

inherited isolated adrenal insufficiency due to partial CYP11A1 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017337

Submitter: Orphanet

Clinical Genomic Database (CGD)

Adrenal insufficiency, congenital, with 46,XY sex reversal, partial or completeAD/AR

Manifestation: Endocrine; Oncologic; Genitourinary

Intervention: Endocrine; Oncologic; Genitourinary

Rationale: Presentation of classic enzymatic deficiency involves adrenal failure and salt wasting in infancy, which can be treatable; Nonclassic forms may present later with some retained adrenal function and abnormal sexual development; Surgical interventions may decrease the risk of gonadal tumors

Refs: 11502818; 12161514; 15507506; 16705068; 18182448; 21159840

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CYP11A1 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 307

Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiencyTotal: 143

Inborn genetic diseasesTotal: 46

not specifiedTotal: 28

CYP11A1-related disorderTotal: 22

21-Hydroxylase-Deficient Congenital Adrenal HyperplasiaTotal: 5

Congenital adrenal hyperplasiaTotal: 3

Differences in sex developmentTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000781.3. 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	142 clinvar	1 clinvar	144
missense	4 clinvar	13 clinvar	123 clinvar	8 clinvar		148
nonsense	18 clinvar	2 clinvar	1 clinvar			21
start loss						0
frameshift	19 clinvar	8 clinvar				27
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar	1 clinvar			6
Total	42	27	126	150	1	346

Highest pathogenic variant AF is 0.000053298892

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000781.3	RefSeq	NP_000772.2	9	MANE Select
ENST00000268053.11	Ensembl	ENSP00000268053.6	9	MANE Select
NM_001099773.2	RefSeq	NP_001093243.1	7	Standard
ENST00000358632.8	Ensembl	ENSP00000351455.4	7	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cyp11a2	Danio rerio	Structure: head Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

cyp11a2

Danio rerio

Structure: head

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

C21-steroid hormone biosynthetic process
glucocorticoid biosynthetic process
cholesterol metabolic process
sterol metabolic process
cortisol metabolic process

Molecular Function

iron ion binding
protein binding
cholesterol monooxygenase (side-chain-cleaving) activity
heme binding

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000268053
Coding exons: 9
Length: 29982
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	0.769	277	315	0.878	0.0000199	3431
Missense (PolyPhen)		94	120.64	0.77917		1323
Synonymous	0.635	118	127	0.928	0.00000797	1036
Loss of Function	2.01	14	24.8	0.564	0.00000151	253

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00027	0.00027	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00021	0.00020	rare
South Asian	0.000098	0.000098	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the side-chain cleavage reaction of cholesterol to pregnenolone, the precursor of most steroid hormones. {ECO:0000269|PubMed:21636783}.;
Disease: DISEASE: Adrenal insufficiency, congenital, with 46,XY sex reversal (AICSR) [MIM:613743]: A rare disorder that can present as acute adrenal insufficiency in infancy or childhood. ACTH and plasma renin activity are elevated and adrenal steroids are inappropriately low or absent; the 46,XY patients have female external genitalia, sometimes with clitoromegaly. The phenotypic spectrum ranges from prematurity, complete underandrogenization, and severe early-onset adrenal failure to term birth with clitoromegaly and later-onset adrenal failure. Patients with congenital adrenal insufficiency do not manifest the massive adrenal enlargement typical of congenital lipoid adrenal hyperplasia. {ECO:0000269|PubMed:11502818, ECO:0000269|PubMed:12161514, ECO:0000269|PubMed:16705068, ECO:0000269|PubMed:18182448, ECO:0000269|PubMed:19116240}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.140

Intolerance Scores

LoFtool: 0.589
RVIS EVS: 0.02
RVIS percentile EVS: 55.61

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.990

Gene Damage Prediction

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