Congenital bile acid synthesis defect 3

Summary

Congenital bile acid synthesis defect 3 (MONDO:0013439) is a disease caused by CYP7B1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CYP7B1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 30
• Phenotypes (HPO): 12

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0000952	Jaundice	Frequent (30-79%)
HP:0001394	Cirrhosis	Frequent (30-79%)
HP:0001396	Cholestasis	Frequent (30-79%)
HP:0001399	Hepatic failure	Frequent (30-79%)
HP:0001408	Bile duct proliferation	Frequent (30-79%)
HP:0001433	Hepatosplenomegaly	Frequent (30-79%)
HP:0002630	Fat malabsorption	Frequent (30-79%)
HP:0002904	Hyperbilirubinemia	Frequent (30-79%)
HP:0003155	Elevated circulating alkaline phosphatase concentration	Frequent (30-79%)
HP:0031956	Elevated circulating aspartate aminotransferase concentration	Frequent (30-79%)
HP:0031964	Elevated circulating alanine aminotransferase concentration	Frequent (30-79%)
HP:0100508	Abnormality of vitamin metabolism	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital bile acid synthesis defect 3
Mondo ID	MONDO:0013439
MeSH	C566340
OMIM	613812
Orphanet	79302
DOID	DOID:0111070
SNOMED CT	719454003
UMLS	C3151147
MedGen	462497
GARD	0016713
Is cancer (heuristic)	no

Also known as: BASD3 · bile acid synthesis defect, congenital, 3 · bile acid synthesis defect, congenital, type 3 · CBAS3 · congenital bile acid synthesis defect caused by mutation in CYP7B1 · congenital bile acid synthesis defect type 3 · CYP7B1 congenital bile acid synthesis defect · oxysterol 7-alpha-hydroxylase deficiency

Data availability: 30 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › steroid inherited metabolic disorder › congenital bile acid synthesis defect › congenital bile acid synthesis defect 3

Related subtypes (5): congenital bile acid synthesis defect 4, congenital bile acid synthesis defect 2, congenital bile acid synthesis defect 1, congenital bile acid synthesis defect 5, congenital bile acid synthesis defect 6

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

30 retrieved; paginated sample, class counts are floors:

8 conflicting classifications of pathogenicity, 7 pathogenic/likely pathogenic, 6 pathogenic, 4 likely pathogenic, 4 uncertain significance, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1335945	NM_004820.5(CYP7B1):c.1081C>T (p.Arg361Ter)	CYP7B1	Pathogenic	criteria provided, multiple submitters, no conflicts
219912	NM_004820.5(CYP7B1):c.334C>T (p.Arg112Ter)	CYP7B1	Pathogenic	criteria provided, multiple submitters, no conflicts
225337	NM_004820.5(CYP7B1):c.259+2T>C	CYP7B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
240073	NM_004820.5(CYP7B1):c.321_324del (p.Lys107fs)	CYP7B1	Pathogenic	criteria provided, multiple submitters, no conflicts
2885037	NM_004820.5(CYP7B1):c.650T>A (p.Leu217Ter)	CYP7B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2983280	NM_004820.5(CYP7B1):c.1233+1G>A	CYP7B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
409026	NM_004820.5(CYP7B1):c.1286dup (p.Lys430fs)	CYP7B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488846	NM_004820.5(CYP7B1):c.187C>T (p.Arg63Ter)	CYP7B1	Pathogenic	criteria provided, multiple submitters, no conflicts
6100	NM_004820.5(CYP7B1):c.1162C>T (p.Arg388Ter)	CYP7B1	Pathogenic	criteria provided, multiple submitters, no conflicts
6103	NM_004820.5(CYP7B1):c.1250G>A (p.Arg417His)	CYP7B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6105	NM_004820.5(CYP7B1):c.825T>A (p.Tyr275Ter)	CYP7B1	Pathogenic	criteria provided, multiple submitters, no conflicts
6107	NM_004820.5(CYP7B1):c.1456C>T (p.Arg486Cys)	CYP7B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
942745	NM_004820.5(CYP7B1):c.961G>A (p.Glu321Lys)	CYP7B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3256740	NM_004820.5(CYP7B1):c.137C>G (p.Pro46Arg)	CYP7B1	Likely pathogenic	no assertion criteria provided
3256741	NM_004820.5(CYP7B1):c.888C>G (p.Asn296Lys)	CYP7B1	Likely pathogenic	no assertion criteria provided
3595818	NM_004820.5(CYP7B1):c.1108C>T (p.Arg370Cys)	CYP7B1	Likely pathogenic	criteria provided, single submitter
4796595	NM_004820.5(CYP7B1):c.122+1G>A	CYP7B1	Likely pathogenic	criteria provided, single submitter
1981100	NM_004820.5(CYP7B1):c.788T>G (p.Val263Gly)	CYP7B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
219384	NM_004820.5(CYP7B1):c.59C>T (p.Pro20Leu)	CYP7B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2585107	NM_004820.5(CYP7B1):c.1109G>A (p.Arg370His)	CYP7B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2863524	NM_004820.5(CYP7B1):c.1082G>A (p.Arg361Gln)	CYP7B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
288705	NM_004820.5(CYP7B1):c.530C>T (p.Thr177Met)	CYP7B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
642794	NM_004820.5(CYP7B1):c.854A>T (p.His285Leu)	CYP7B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
942744	NM_004820.5(CYP7B1):c.1346G>A (p.Cys449Tyr)	CYP7B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
962151	NM_004820.5(CYP7B1):c.1457G>A (p.Arg486His)	CYP7B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3595817	NM_004820.5(CYP7B1):c.1280C>T (p.Thr427Ile)	CYP7B1	Uncertain significance	criteria provided, single submitter
3595819	NM_004820.5(CYP7B1):c.1001G>C (p.Gly334Ala)	CYP7B1	Uncertain significance	criteria provided, single submitter
595578	NM_004820.5(CYP7B1):c.350A>C (p.Lys117Thr)	CYP7B1	Uncertain significance	criteria provided, multiple submitters, no conflicts
598140	NM_004820.5(CYP7B1):c.17C>G (p.Ser6Cys)	CYP7B1	Uncertain significance	criteria provided, multiple submitters, no conflicts
282111	NM_004820.5(CYP7B1):c.122+19A>T	CYP7B1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CYP7B1	Strong	Autosomal recessive	congenital bile acid synthesis defect 3	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYP7B1	Orphanet:100986	Autosomal recessive spastic paraplegia type 5A
CYP7B1	Orphanet:79302	Congenital bile acid synthesis defect type 3

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CYP7B1	HGNC:2652	ENSG00000172817	O75881	Cytochrome P450 7B1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYP7B1	Cytochrome P450 7B1	A cytochrome P450 monooxygenase involved in the metabolism of endogenous oxysterols and steroid hormones, including neurosteroids.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYP7B1	Enzyme (other)	yes	1.14.14.29	Cyt_P450, Cyt_P450_E_grp-IV, Cyt_P450_CYP7A1-type

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
esophagus squamous epithelium	1
oral cavity	1
seminal vesicle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYP7B1	239	broad	marker	seminal vesicle, oral cavity, esophagus squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CYP7B1	1,891

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CYP7B1	O75881	91.98

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective CYP7B1 causes SPG5A and CBAS3	1	11420.0×	4e-04	CYP7B1
Synthesis of bile acids and bile salts via 27-hydroxycholesterol	1	761.3×	0.003	CYP7B1
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	456.8×	0.003	CYP7B1
Synthesis of bile acids and bile salts	1	407.9×	0.003	CYP7B1
Endogenous sterols	1	393.8×	0.003	CYP7B1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
B cell chemotaxis	1	2808.7×	0.003	CYP7B1
prostate gland epithelium morphogenesis	1	1872.4×	0.003	CYP7B1
negative regulation of intracellular estrogen receptor signaling pathway	1	1123.5×	0.003	CYP7B1
sterol metabolic process	1	842.6×	0.003	CYP7B1
estrogen receptor signaling pathway	1	732.7×	0.003	CYP7B1
bile acid biosynthetic process	1	624.1×	0.003	CYP7B1
steroid biosynthetic process	1	601.9×	0.003	CYP7B1
epithelial cell proliferation	1	312.1×	0.004	CYP7B1
positive regulation of epithelial cell proliferation	1	244.2×	0.005	CYP7B1
cholesterol metabolic process	1	195.9×	0.006	CYP7B1
cholesterol homeostasis	1	156.0×	0.006	CYP7B1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYP7B1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CYP7B1	2	ADMET:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYP7B1	1.14.14.29	25/26-hydroxycholesterol 7alpha-hydroxylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	CYP7B1
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CYP7B1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.