CYP7B1

protein-coding

cytochrome P450 family 7 subfamily B member 1, the group of Cytochrome P450 family 7

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 endoplasmic reticulum membrane protein catalyzes the first reaction in the cholesterol catabolic pathway of extrahepatic tissues, which converts cholesterol to bile acids. This enzyme likely plays a minor role in total bile acid synthesis, but may also be involved in the development of atherosclerosis, neurosteroid metabolism and sex hormone synthesis. Mutations in this gene have been associated with hereditary spastic paraplegia (SPG5 or HSP), an autosomal recessive disorder. [provided by RefSeq, Apr 2016]

Previous symbols:

SPG5A

MANE transcript

NM_004820.5

Inheritance

ClinVar variants

P:100U:223B:169

Top phenotype

Bile acid synthesis defect, congenital, 3

gnomAD constraint

pLI —, LoF o/e 0.57

Max pathogenic AF

—

Genomic locus

chr8:64,587,763-64,798,737

External References & Databases

Ensembl (ENSG00000172817)

Transcript & Mutation Effects

hg38 • Region Span ~211.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital bile acid synthesis defect 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013439

Submitter: Labcorp Genetics (formerly Invitae)

CYP7B1-related disorder of oxysterol accumulationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:1060107

Submitter: ClinGen

**CYP7B1, CYP7B1-related disorder of oxysterol accumulation (http://purl.obolibrary.org/obo/MONDO_1060107), autosomal recessive** CYP7B1 was first described as a congenital bile acid synthesis disorder-causing gene in 1998 (Setchell et al. 1998, PMID: 9802883). The specific disease entity, congenital bile acid synthesis disorder (http://purl.obolibrary.org/obo/MONDO_1060107, OMIM:603711), is one of at least 6 forms of congenital bile acid synthesis defects. Some of the most common patient phenotypes are: Elevated circulating alanine aminotransferase concentration, Jaundice and one case of Prolonged neonatal jaundice, Elevated circulating aspartate aminotransferase concentration, Hepatosplenomegaly and Elevated Oxysterol Levels. CYP7B1 was first described as a spastic paraplegia-causing gene in 2008 (Tsaousidou et al. 2008, PMID: 18252231). The specific disease entity, CYP7B1-related disorder of oxysterol accumulation (http://purl.obolibrary.org/obo/MONDO_1060107, OMIM:603711), is one of at least 100 spastic paraplegia disorders. Some of the most common patient phenotypes are: Affected/abnormal white brain matter, Lower limb spasticity, Lower limb hyperreflexia, Babinski sign, Increased total bilirubin, Impaired vibratory sensation, Upper limb hyperreflexia, Lower limb muscle weakness, Prolonged prothrombin time, and Elevated Oxysterol Levels. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance (autosomal recessive) and molecular mechanism (CYP7B1 loss-of-function) were found to be consistent between the congenital bile acid synthesis defect 3 cases and the spastic paraplegia 5A cases. In addition, the shared feature of elevated oxysterol levels observed in both groups of patients appeared to represent a single spectrum of disease. Therefore, cases caused by inherited CYP7B1 variants have been lumped for the purposes of gene curation into a single disease entity referred to as "CYP7B1-related disorder of oxysterol accumulation". Thirteen variants: (4 types of genetic mutations: Nonsense (3), Missense (6), Splice Site (1) & Frameshift (3)) that have been reported in 14 probands in 13 publications (PMIDs: 9802883, 18252231, 12874406, 19187859, 19439420, 21214876, 24658845, 33849447, 24509641, 30546280, 35387662, 30333426, 21567895) are included in this curation. The age of onset and diagnosis was highly variable among the probands. Probands with symptoms of bile acid synthesis tended to have congenital onset and require treatment whereas probands with spastic paraplegia tended to have milder, adult onset. A few probands appeared to display a combination of bile acid synthesis and spastic paraplegia phenotypes. Siblings of the probands were also found to be affected to varying degrees of severity. Some siblings were found to have symptoms of spastic paraplegia while the affected proband displayed bile acid synthesis phenotypes. There were also instances where siblings were found to have symptoms of bile acid synthesis while the affected proband displayed spastic paraplegia phenotypes. Overall, the mechanism of pathogenicity appears to be loss of function as shown in the types of variants harbored by the probands. This gene-disease relationship is also supported by multiple forms of experimental evidence such as BioChem B (Quantity: 1), Model System: Mouse (Mus musculus) (Quantity: 2) (PMIDs: 19687010, 10748048 and 31013940). First, Stiles et al. 2009 (PMID: 19687010), the affected oxysterol 7-alpha-hydroxylase activity recapitulates what is seen in the human probands. Next, Li-Hawkins et al. 2000 had a knockout mouse that showed affected oxysterol activity which recapitulates what is seen in the human probands. Meljon et al. 2019 also had a knockout mouse that showed the same phenotype (PMID: 31013940). In conclusion, CYP7B1 is definitively associated with CYP7B1-related disorder of oxysterol accumulation. This classification has been clearly demonstrated and confirmed through both experimental and genetic evidence and has been upheld over time. This classification was approved by the General IEM GCEP on February 28th, 2025 (SOP Version 11).

hereditary spastic paraplegia 5ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010047

Submitter: Labcorp Genetics (formerly Invitae)

congenital bile acid synthesis defect 3SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013439

Submitter: Orphanet

congenital bile acid synthesis defect 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013439

Submitter: Ambry Genetics

hereditary spastic paraplegia 5ASUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010047

Submitter: Orphanet

hereditary spastic paraplegia 5ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010047

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Bile acid synthesis defect, congenital, 3AR

Manifestation: Gastrointestinal; Neurologic

Intervention: Gastrointestinal

Rationale: Individuals may manifest with early-onset, progressive and severe cholestatic liver disease, and early recognition may allow treatment; Liver transplanation has been described

Refs: 7987300; 9802883; 18252231; 19187859; 19439420; 21567895; 21623769; 22384504

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CYP7B1 variants in ClinVar

10 Conditions Cataloged

Spastic paraplegiaTotal: 462

not providedTotal: 135

CYP7B1-related disorderTotal: 90

Hereditary spastic paraplegia 5ATotal: 76

Inborn genetic diseasesTotal: 64

not specifiedTotal: 32

Congenital bile acid synthesis defect 3Total: 30

Hereditary spastic paraplegiaTotal: 29

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004820.5. 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			5 clinvar	157 clinvar		162
missense	5 clinvar	27 clinvar	215 clinvar	10 clinvar	2 clinvar	259
nonsense	18 clinvar	5 clinvar	1 clinvar			24
start loss		1 clinvar				1
frameshift	26 clinvar	10 clinvar	1 clinvar			37
splice donor/acceptor (+/-2bp)	1 clinvar	7 clinvar	1 clinvar			9
Total	50	50	223	167	2	492

Highest pathogenic variant AF is 0.0007772531

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004820.5	RefSeq	NP_004811.1	6	MANE Select
ENST00000310193.4	Ensembl	ENSP00000310721.3	6	MANE Select
NM_001324112.2	RefSeq	NP_001311041.1	7	Standard
ENST00000864435.1	Ensembl	ENSP00000534494.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Steroid hormone biosynthesis - Homo sapiens (human)
Primary bile acid biosynthesis - Homo sapiens (human)
27-Hydroxylase Deficiency
Bile Acid Biosynthesis
Congenital Bile Acid Synthesis Defect Type II

Biological Process

bile acid biosynthetic process
cholesterol metabolic process
sterol metabolic process
negative regulation of intracellular estrogen receptor signaling pathway
B cell chemotaxis

Molecular Function

iron ion binding
oxysterol 7-alpha-hydroxylase activity
heme binding

Cellular Component

endoplasmic reticulum membrane
organelle membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000310193
Coding exons: 6
Length: 210999
Individuals with no LoFs: 125724
Homozygous LoFs: 0
Heterozygous LoFs: 24
Defined: 125748
p: 0.0000954

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.395	272	254	1.07	0.0000126	3298
Missense (PolyPhen)		95	96.978	0.9796		1267
Synonymous	-1.66	114	93.5	1.22	0.00000468	963
Loss of Function	1.80	12	20.9	0.575	0.00000123	258

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00033	0.00033	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000097	0.000097	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Oxysterol 7alpha-hydroxylase that mediates formation of 7-alpha,25-dihydroxycholesterol (7-alpha,25-OHC) from 25- hydroxycholesterol (PubMed:10588945). Plays a key role in cell positioning and movement in lymphoid tissues: 7-alpha,25- dihydroxycholesterol (7-alpha,25-OHC) acts as a ligand for the G protein-coupled receptor GPR183/EBI2, a chemotactic receptor for a number of lymphoid cells (By similarity). {ECO:0000250|UniProtKB:Q60991, ECO:0000269|PubMed:10588945}.;
Disease: DISEASE: Congenital bile acid synthesis defect 3 (CBAS3) [MIM:613812]: A disorder resulting in severe cholestasis, cirrhosis and liver synthetic failure. Hepatic microsomal oxysterol 7-alpha-hydroxylase activity is undetectable. {ECO:0000269|PubMed:9802883}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.245

Intolerance Scores

LoFtool: 0.480
RVIS EVS: -0.36
RVIS percentile EVS: 28.93

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.251

Gene Damage Prediction

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