Hypercholanemia, familial, 2

Summary

Hypercholanemia, familial, 2 (MONDO:0031003) is a disease caused by SLC10A1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SLC10A1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 18

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypercholanemia, familial, 2
Mondo ID	MONDO:0031003
OMIM	619256
DOID	DOID:0061182
UMLS	C5543243
MedGen	1780531
GARD	0018341
Is cancer (heuristic)	no

Also known as: FHCA2 · hypercholanemia, familial 2 · NTCP Deficiency

Data availability: 18 ClinVar variants · 2 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 › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of bile acid synthesis › hypercholanemia, familial › hypercholanemia, familial, 2

Related subtypes (1): hypercholanemia, familial 1

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

18 retrieved; paginated sample, class counts are floors:

8 conflicting classifications of pathogenicity, 7 uncertain significance, 2 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1705419	NM_003049.4(SLC10A1):c.713_717del (p.Tyr238fs)	SLC10A1	Likely pathogenic	criteria provided, single submitter
4849384	NM_003049.4(SLC10A1):c.356+2T>G	SLC10A1	Likely pathogenic	criteria provided, single submitter
2634275	NM_003049.4(SLC10A1):c.568-1G>A	SLC10A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3796369	NM_003049.4(SLC10A1):c.592T>C (p.Cys198Arg)	SLC10A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
500821	NM_003049.4(SLC10A1):c.104T>A (p.Leu35Ter)	SLC10A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
501461	NM_003049.4(SLC10A1):c.800C>T (p.Ser267Phe)	SLC10A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
501945	NM_003049.4(SLC10A1):c.755G>A (p.Arg252His)	SLC10A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
502734	NM_003049.4(SLC10A1):c.664_665del (p.Leu222fs)	SLC10A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
594495	NM_003049.4(SLC10A1):c.34_38del (p.Phe12fs)	SLC10A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
595168	NM_003049.4(SLC10A1):c.132C>A (p.Cys44Ter)	SLC10A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2435962	NM_003049.4(SLC10A1):c.603C>T (p.Ala201=)	SLC10A1	Uncertain significance	criteria provided, single submitter
2444366	NM_003049.4(SLC10A1):c.806T>G (p.Ile269Ser)	SLC10A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2634835	NM_003049.4(SLC10A1):c.102GTT[1] (p.Leu35del)	SLC10A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3065639	NM_003049.4(SLC10A1):c.71A>C (p.Asp24Ala)	SLC10A1	Uncertain significance	criteria provided, single submitter
3780605	NM_003049.4(SLC10A1):c.747-7G>A	SLC10A1	Uncertain significance	criteria provided, single submitter
594061	NM_003049.4(SLC10A1):c.559G>C (p.Val187Leu)	SLC10A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
597217	NM_003049.4(SLC10A1):c.122C>T (p.Ser41Leu)	SLC10A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
598530	NM_003049.4(SLC10A1):c.263T>C (p.Ile88Thr)	SLC10A1	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 1 · 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
SLC10A1	Strong	Autosomal recessive	hypercholanemia, familial, 2	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC10A1	Orphanet:238475	Familial hypercholanemia

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
SLC10A1	HGNC:10905	ENSG00000100652	Q14973	Hepatic sodium/bile acid cotransporter	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC10A1	Hepatic sodium/bile acid cotransporter	As a major transporter of conjugated bile salts from plasma into the hepatocyte, it plays a key role in the enterohepatic circulation of bile salts necessary for the solubilization and absorption of dietary fat and fat-soluble vitamins.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC10A1	Other/Unknown	no		BilAc:Na_symport/Acr3, Bilac:Na_transpt, Na+/solute_symporter_sf

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
left ventricle myocardium	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC10A1	74	tissue_specific	marker	right lobe of liver, liver, left ventricle myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC10A1	2,033

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC10A1	Q14973	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Recycling of bile acids and salts	1	601.0×	0.002	SLC10A1

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
bile acid and bile salt transport	1	648.1×	0.005	SLC10A1
response to nutrient levels	1	366.4×	0.005	SLC10A1
response to estrogen	1	343.9×	0.005	SLC10A1
cellular response to xenobiotic stimulus	1	240.7×	0.005	SLC10A1
response to ethanol	1	146.5×	0.007	SLC10A1

Therapeutics

Drug target analysis

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

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

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SLC10A1	EZETIMIBE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC10A1	15	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EZETIMIBE	4	SLC10A1
ROSIGLITAZONE	4	SLC10A1
IRBESARTAN	4	SLC10A1
URSODIOL	4	SLC10A1
CYCLOSPORINE	4	SLC10A1
RITONAVIR	4	SLC10A1
FLUVASTATIN	4	SLC10A1
PROPRANOLOL	4	SLC10A1
FUROSEMIDE	4	SLC10A1
SULFASALAZINE	4	SLC10A1
ZAFIRLUKAST	4	SLC10A1
CURCUMIN	3	SLC10A1
FASIGLIFAM	3	SLC10A1
TIRATRICOL	3	SLC10A1
LEVOPROPRANOLOL	2	SLC10A1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC10A1	78	Binding:53, Functional:25

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

15 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.

Compound	Max phase	Cohort target (bioactivity)
EZETIMIBE	4	SLC10A1
ROSIGLITAZONE	4	SLC10A1
IRBESARTAN	4	SLC10A1
URSODIOL	4	SLC10A1
CYCLOSPORINE	4	SLC10A1
RITONAVIR	4	SLC10A1
FLUVASTATIN	4	SLC10A1
PROPRANOLOL	4	SLC10A1
FUROSEMIDE	4	SLC10A1
SULFASALAZINE	4	SLC10A1
ZAFIRLUKAST	4	SLC10A1
CURCUMIN	3	SLC10A1
FASIGLIFAM	3	SLC10A1
TIRATRICOL	3	SLC10A1
LEVOPROPRANOLOL	2	SLC10A1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SLC10A1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.