CYP27A1

protein-coding

cytochrome P450 family 27 subfamily A member 1, the group of Cytochrome P450 family 27

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 mitochondrial protein oxidizes cholesterol intermediates as part of the bile synthesis pathway. Since the conversion of cholesterol to bile acids is the major route for removing cholesterol from the body, this protein is important for overall cholesterol homeostasis. Mutations in this gene cause cerebrotendinous xanthomatosis, a rare autosomal recessive lipid storage disease. [provided by RefSeq, Jul 2008]

Previous symbols:

CYP27

MANE transcript

NM_000784.4

Inheritance

ClinVar variants

P:247U:425B:389

Top phenotype

Cerebrotendinous xanthomatosis

gnomAD constraint

pLI —, LoF o/e 1

Max pathogenic AF

—

Genomic locus

chr2:218,781,749-218,815,293

External References & Databases

Ensembl (ENSG00000135929)

Transcript & Mutation Effects

hg38 • Region Span ~33.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cerebrotendinous xanthomatosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008948

Submitter: G2P

cerebrotendinous xanthomatosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008948

Submitter: Labcorp Genetics (formerly Invitae)

cerebrotendinous xanthomatosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008948

Submitter: Natera

cerebrotendinous xanthomatosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008948

Submitter: ClinGen

The CYP27A1 gene encodes sterol 27-hydroxylase, an enzyme that is part of the bile acid biosynthesis pathway, specifically involved in the metabolism of cholesterol and bile acids. CYP27A1 was first reported in relation to autosomal recessive cerebrotendinous xanthomatosis (CTX) in 1991 (Cali et al. PMID: 2019602). CTX is a lipid storage disease clinically characterized by diarrhea in infancy, cataracts onset in childhood, tendon xanthomas appearing in adolescence or early adulthood, and adult-onset progressive neurologic dysfunction (psychiatric symptoms, dementia, pyramidal and/or cerebellar signs, dystonia, atypical parkinsonism, peripheral neuropathy, and seizures). Brain MRI findings include white matter signal abnormalities, diffuse brain and cerebellar atrophy, and bilateral hyperintensity of the dentate nuclei. CTX is biochemically characterized by severely reduced levels of chenodeoxycholic acid (CDCA), accumulation of cholesterol and cholestanol in tissues, and increased excretion of bile acids in urine. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, the single disease entity has been maintained: cerebrotendinous xanthomatosis (OMIM#606530). This curation included one missense, three frameshift, one nonsense, and three splice variants reported in eight probands across five publications (PMIDs:7977352, 33400472, 7860076, 31706903, 26937392). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by biochemical function evidence (PMID: 16816916). In summary, there is definitive evidence supporting the relationship between CYP27A1 and autosomal recessive cerebrotendinous xanthomatosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date: September 23, 2024 SOP Version #11.

cerebrotendinous xanthomatosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008948

Submitter: Genomics England PanelApp

cerebrotendinous xanthomatosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008948

Submitter: Orphanet

cerebrotendinous xanthomatosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008948

Submitter: Myriad Women's Health

Clinical Genomic Database (CGD)

Cerebrotendinous xanthomatosisAR

Manifestation: Biochemical; Cardiovascular; Gastrointestinal; Neurologic; Ophthalmologic

Intervention: Biochemical; Cardiovascular

Rationale: The condition manifests with progressive neurologic dysfunction, as well as cardiovascular and ophthalmologic dysfunction, and medical treatment (eg, with chenodeoxycholic acid and HMG-CoA reductase inhibitors) can be beneficial

Refs: 5636664; 5676919; 5355255; 4825231; 7315872; 7298854; 6504105; 3106810; 3128689; 1708392; 7847220; 7964884; 10430841; 11804206; 12555943; 11939886; 16278884; 18227423; 20301583; 20402754; 20450308; 20558929; 21553098; 22018287; 22336472; 23375591

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CYP27A1 variants in ClinVar

10 Conditions Cataloged

Cholestanol storage diseaseTotal: 1098

Cardiovascular phenotypeTotal: 322

not providedTotal: 248

CYP27A1-related disorderTotal: 155

not specifiedTotal: 80

Intellectual disabilityTotal: 4

Senior-Loken syndrome 1Total: 1

Regression of motor development with severe dystonia and corresponding basal ganglia lesionsTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000784.4. 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	2 clinvar	7 clinvar	352 clinvar	4 clinvar	366
missense	13 clinvar	27 clinvar	411 clinvar	32 clinvar	1 clinvar	484
nonsense	32 clinvar	29 clinvar	2 clinvar			63
start loss	1 clinvar	4 clinvar				5
frameshift	44 clinvar	52 clinvar	5 clinvar			101
splice donor/acceptor (+/-2bp)	21 clinvar	21 clinvar				42
Total	112	135	425	384	5	1061

Highest pathogenic variant AF is 0.00042378026

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000784.4	RefSeq	NP_000775.1	9	MANE Select
ENST00000258415.9	Ensembl	ENSP00000258415.4	9	MANE Select
ENST00000411688.1	Ensembl	ENSP00000392671.1	4	Standard
ENST00000445971.1	Ensembl	ENSP00000404945.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cholesterol metabolism - Homo sapiens (human)
Primary bile acid biosynthesis - Homo sapiens (human)
PPAR signaling pathway - Homo sapiens (human)
27-Hydroxylase Deficiency
Bile Acid Biosynthesis

Biological Process

bile acid biosynthetic process
sterol metabolic process
oxidation-reduction process

Molecular Function

iron ion binding
steroid hydroxylase activity
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen
heme binding

Cellular Component

mitochondrion
mitochondrial matrix
mitochondrial membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000258415
Coding exons: 9
Length: 33545
Individuals with no LoFs: 125591
Homozygous LoFs: 0
Heterozygous LoFs: 157
Defined: 125748
p: 0.000624

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.310	319	304	1.05	0.0000186	3416
Missense (PolyPhen)		102	94.918	1.0746		1011
Synonymous	0.294	126	130	0.967	0.00000808	1087
Loss of Function	-0.0185	28	27.9	1.00	0.00000167	275

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00068	0.00068	rare
Latino/Admixed American	0.00055	0.00055	rare
Ashkenazi Jewish	0.0011	0.0011	notable
East Asian	0.00071	0.00071	rare
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00048	0.00048	rare
South Asian	0.0013	0.0013	notable
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the first step in the oxidation of the side chain of sterol intermediates; the 27-hydroxylation of 5-beta- cholestane-3-alpha,7-alpha,12-alpha-triol. Has also a vitamin D3- 25-hydroxylase activity. {ECO:0000250|UniProtKB:P17177}.;
Disease: DISEASE: Cerebrotendinous xanthomatosis (CTX) [MIM:213700]: Rare sterol storage disorder characterized clinically by progressive neurologic dysfunction, premature atherosclerosis, and cataracts. {ECO:0000269|PubMed:12000359, ECO:0000269|PubMed:2019602, ECO:0000269|PubMed:7915755, ECO:0000269|PubMed:9186905, ECO:0000269|PubMed:9790667}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.449

Intolerance Scores

LoFtool: 0.705
RVIS EVS: -0.31
RVIS percentile EVS: 32.23

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.900

Gene Damage Prediction

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