Cholestasis, progressive familial intrahepatic, 7, with or without hearing loss

Summary

Cholestasis, progressive familial intrahepatic, 7, with or without hearing loss (MONDO:0030503) is a disease caused by USP53 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: USP53 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 39

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cholestasis, progressive familial intrahepatic, 7, with or without hearing loss
Mondo ID	MONDO:0030503
OMIM	619658
UMLS	C5562043
MedGen	1794253
GARD	0025583
Is cancer (heuristic)	no

Also known as: PFIC7

Data availability: 39 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › progressive familial intrahepatic cholestasis › cholestasis, progressive familial intrahepatic, 7, with or without hearing loss

Related subtypes (15): progressive familial intrahepatic cholestasis type 1, benign recurrent intrahepatic cholestasis type 1, progressive familial intrahepatic cholestasis type 2, progressive familial intrahepatic cholestasis type 3, hereditary North American Indian childhood cirrhosis, cholestasis, progressive familial intrahepatic, 4, cholestasis, progressive familial intrahepatic, 5, MYO5B-related progressive familial intrahepatic cholestasis, cholestasis, progressive familial intrahepatic, 6, cholestasis, progressive familial intrahepatic, 8, cholestasis, progressive familial intrahepatic, 9, cholestasis, progressive familial intrahepatic, 10, cholestasis, progressive familial intrahepatic, 11, cholestasis, progressive familial intrahepatic, 12, cholestasis, progressive familial intrahepatic, 13

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

39 retrieved; paginated sample, class counts are floors:

16 likely pathogenic, 12 pathogenic, 7 uncertain significance, 2 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1328227	NM_001371395.1(USP53):c.951del (p.Phe317fs)	USP53	Pathogenic	criteria provided, single submitter
1328232	NM_001371395.1(USP53):c.725C>T (p.Pro242Leu)	USP53	Pathogenic	no assertion criteria provided
1328233	NM_001371395.1(USP53):c.510del (p.Ser171fs)	USP53	Pathogenic	criteria provided, single submitter
1686292	NM_001371395.1(USP53):c.1687del (p.Ser563fs)	USP53	Pathogenic	criteria provided, single submitter
2572008	NM_001371395.1(USP53):c.1744C>T (p.Arg582Ter)	USP53	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2692225	NM_001371395.1(USP53):c.153G>A (p.Trp51Ter)	USP53	Pathogenic	criteria provided, single submitter
3370325	NM_001371395.1(USP53):c.1069dup (p.Ser357fs)	USP53	Pathogenic	criteria provided, single submitter
3572956	NM_001371395.1(USP53):c.1219A>T (p.Lys407Ter)	USP53	Pathogenic	criteria provided, single submitter
694273	NM_001371395.1(USP53):c.1012C>T (p.Arg338Ter)	USP53	Pathogenic	criteria provided, multiple submitters, no conflicts
694473	NM_001371395.1(USP53):c.169C>T (p.Arg57Ter)	USP53	Pathogenic	criteria provided, single submitter
694474	NM_001371395.1(USP53):c.297G>T (p.Arg99Ser)	USP53	Pathogenic	criteria provided, single submitter
694477	NM_001371395.1(USP53):c.583del (p.Arg195fs)	USP53	Pathogenic	criteria provided, single submitter
694480	NM_001371395.1(USP53):c.1426C>T (p.Arg476Ter)	USP53	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
694481	NM_001371395.1(USP53):c.1558C>T (p.Arg520Ter)	USP53	Pathogenic	criteria provided, multiple submitters, no conflicts
4057271	Single allele	ARLN	Likely pathogenic	criteria provided, single submitter
1333554	NM_001371395.1(USP53):c.205C>T (p.Gln69Ter)	USP53	Likely pathogenic	criteria provided, single submitter
1526033	NM_001371395.1(USP53):c.158T>A (p.Leu53Ter)	USP53	Likely pathogenic	criteria provided, single submitter
1526171	NM_001371395.1(USP53):c.331C>T (p.Arg111Ter)	USP53	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705415	NM_001371395.1(USP53):c.972+3_972+6del	USP53	Likely pathogenic	criteria provided, single submitter
1705494	NM_001371395.1(USP53):c.973-1G>A	USP53	Likely pathogenic	criteria provided, single submitter
1705629	NM_001371395.1(USP53):c.78_79dup (p.Ala27fs)	USP53	Likely pathogenic	criteria provided, single submitter
2434496	NM_001371395.1(USP53):c.829del (p.Tyr277fs)	USP53	Likely pathogenic	criteria provided, single submitter
2584943	NM_001371395.1(USP53):c.1295_1299del (p.Leu432fs)	USP53	Likely pathogenic	criteria provided, single submitter
2585608	NM_001371395.1(USP53):c.822+1del	USP53	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2671669	NM_001371395.1(USP53):c.237+1G>A	USP53	Likely pathogenic	criteria provided, single submitter
2671670	NM_001371395.1(USP53):c.570-1G>A	USP53	Likely pathogenic	criteria provided, single submitter
3064438	NM_001371395.1(USP53):c.145-10_168del	USP53	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3601992	NM_001371395.1(USP53):c.9G>A (p.Trp3Ter)	USP53	Likely pathogenic	criteria provided, single submitter
3764647	NM_001371395.1(USP53):c.336del (p.Gln113fs)	USP53	Likely pathogenic	criteria provided, single submitter
3773690	NM_001371395.1(USP53):c.136G>T (p.Ala46Ser)	USP53	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 0 · 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
USP53	Strong	Autosomal recessive	cholestasis	3

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
USP53	HGNC:29255	ENSG00000145390	Q70EK8	Ubiquitin carboxyl-terminal hydrolase 53	gencc,clinvar
ARLN	HGNC:19225	ENSG00000164096	Q8WVX3	Sarcoplasmic/endoplasmic reticulum calcium ATPase regulator ARLN	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
USP53	Ubiquitin carboxyl-terminal hydrolase 53	Deubiquitinase that mediates ‘Lys-63’-linked deubiquitination of tight junction proteins, such as MARVELD2 and LSR, and which is involved in the survival of auditory hair cells and hearing.
ARLN	Sarcoplasmic/endoplasmic reticulum calcium ATPase regulator ARLN	Inhibits the activity of the calcium ATPases ATP2A2/SERCA2 and ATP2A3/SERCA3 by decreasing their apparent affinity for Ca(2+).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Protease	1	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
USP53	Protease	yes		Peptidase_C19_UCH, USP, Papain-like_cys_pep_sf
ARLN	Other/Unknown	no		ALN

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
mucosa of stomach	1
tibial nerve	1
endothelial cell	1
inferior vagus X ganglion	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
USP53	269	ubiquitous	marker	calcaneal tendon, tibial nerve, mucosa of stomach
ARLN	256	ubiquitous	marker	endothelial cell, upper arm skin, inferior vagus X ganglion

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
USP53	927
ARLN	306

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARLN	Q8WVX3	68.78
USP53	Q70EK8	55.34

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

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
outer hair cell apoptotic process	1	5617.3×	0.001	USP53
epithelial cell apoptotic process	1	842.6×	0.003	USP53
response to auditory stimulus	1	732.7×	0.003	USP53
action potential	1	358.6×	0.004	USP53
protein deubiquitination	1	177.4×	0.007	USP53
sensory perception of sound	1	100.9×	0.010	USP53

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
USP53	0	0
ARLN	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	USP53
E	Difficult family or no structure, no drug	1	ARLN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
USP53	0	—
ARLN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.