Liddle syndrome 3

Summary

Liddle syndrome 3 (MONDO:0029132) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 141

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Liddle syndrome 3
Mondo ID	MONDO:0029132
OMIM	618126
UMLS	C4748292
MedGen	1648443
GARD	0025502
Is cancer (heuristic)	no

Also known as: Liddle syndrome 3 · LIDLS3

Data availability: 141 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Liddle syndrome › Liddle syndrome 3

Related subtypes (2): Liddle syndrome 1, Liddle syndrome 2

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

141 retrieved; paginated sample, class counts are floors:

109 uncertain significance, 10 conflicting classifications of pathogenicity, 5 pathogenic, 5 likely pathogenic, 4 benign/likely benign, 3 benign, 3 likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3024263	NM_001038.6(SCNN1A):c.1361-3C>G	SCNN1A	Pathogenic	criteria provided, single submitter
3575087	NM_001038.6(SCNN1A):c.1474C>T (p.Arg492Ter)	SCNN1A	Pathogenic	criteria provided, multiple submitters, no conflicts
3575134	NM_001038.6(SCNN1A):c.505_506del (p.Thr169fs)	SCNN1A	Pathogenic	criteria provided, multiple submitters, no conflicts
450202	NM_001038.6(SCNN1A):c.875+1G>A	SCNN1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
802813	NM_001038.6(SCNN1A):c.1439+1G>A	SCNN1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9265	NM_001038.6(SCNN1A):c.1449del (p.Tyr484fs)	SCNN1A	Pathogenic	criteria provided, multiple submitters, no conflicts
988230	NM_001038.6(SCNN1A):c.574del (p.Arg192fs)	SCNN1A	Pathogenic	criteria provided, multiple submitters, no conflicts
3575109	NM_001038.6(SCNN1A):c.979+1G>A	SCNN1A	Likely pathogenic	criteria provided, single submitter
3575110	NM_001038.6(SCNN1A):c.979G>T (p.Gly327Cys)	SCNN1A	Likely pathogenic	criteria provided, single submitter
3575118	NM_001038.6(SCNN1A):c.685-1G>A	SCNN1A	Likely pathogenic	criteria provided, single submitter
3780584	NM_001038.6(SCNN1A):c.33dup (p.Ser12Ter)	SCNN1A	Likely pathogenic	criteria provided, single submitter
591450	NM_001038.6(SCNN1A):c.69del (p.Asn24fs)	SCNN1A	Likely pathogenic	criteria provided, single submitter
229237	NM_001038.6(SCNN1A):c.997C>T (p.Arg333Cys)	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
229238	NM_001038.6(SCNN1A):c.1216C>A (p.Leu406Ile)	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2603120	NM_001038.6(SCNN1A):c.1168G>A (p.Asp390Asn)	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310134	NM_001038.6(SCNN1A):c.1559G>C (p.Gly520Ala)	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310149	NM_001038.6(SCNN1A):c.746G>A (p.Arg249Lys)	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3366612	NM_001038.6(SCNN1A):c.1109G>A (p.Arg370Gln)	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3575096	NM_001038.6(SCNN1A):c.1144-14A>G	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
561216	NM_001038.6(SCNN1A):c.1435T>C (p.Cys479Arg)	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
632197	NM_001038.6(SCNN1A):c.1771C>T (p.Arg591Ter)	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
9264	NM_001038.6(SCNN1A):c.1522C>T (p.Arg508Ter)	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3575156	NM_001038.6(SCNN1A):c.-55+1G>A	LTBR	Uncertain significance	criteria provided, single submitter
1048766	NM_001038.6(SCNN1A):c.457A>T (p.Ile153Phe)	SCNN1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1331718	NM_001038.6(SCNN1A):c.1426C>T (p.Arg476Trp)	SCNN1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1923102	NM_001038.6(SCNN1A):c.1246_1281dup (p.Lys427_Glu428insCysIleHisSerCysPheGlnGluSerMetIleLys)	SCNN1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1953437	NM_001038.6(SCNN1A):c.128C>T (p.Ala43Val)	SCNN1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2056764	NM_001038.6(SCNN1A):c.1772G>A (p.Arg591Gln)	SCNN1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2168610	NM_001038.6(SCNN1A):c.1361G>T (p.Gly454Val)	SCNN1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2349602	NM_001038.6(SCNN1A):c.758G>A (p.Arg253His)	SCNN1A	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 4 · 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
SCNN1A	Supportive	Autosomal dominant	Liddle syndrome	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCNN1A	Orphanet:130	Brugada syndrome
SCNN1A	Orphanet:171876	Generalized pseudohypoaldosteronism type 1
SCNN1A	Orphanet:526	Liddle syndrome
SCNN1A	Orphanet:60033	Idiopathic bronchiectasis

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
SCNN1A	HGNC:10599	ENSG00000111319	P37088	Epithelial sodium channel subunit alpha	gencc,clinvar
LTBR	HGNC:6718	ENSG00000111321	P36941	Tumor necrosis factor receptor superfamily member 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCNN1A	Epithelial sodium channel subunit alpha	This is one of the three pore-forming subunits of the heterotrimeric epithelial sodium channel (ENaC), a critical regulator of sodium balance and fluid homeostasis.
LTBR	Tumor necrosis factor receptor superfamily member 3	Receptor for the heterotrimeric lymphotoxin containing LTA and LTB, and for TNFS14/LIGHT.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCNN1A	Other/Unknown	no		ENaC, ENaC_chordates, ENaC_CS
LTBR	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_3_LTBR, TNFRSF3_N

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
metanephros cortex	1
nasal cavity epithelium	1
right uterine tube	1
left lobe of thyroid gland	1
lower esophagus mucosa	1
right lobe of thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCNN1A	283	broad	marker	nasal cavity epithelium, metanephros cortex, right uterine tube
LTBR	250	ubiquitous	marker	lower esophagus mucosa, right lobe of thyroid gland, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LTBR	1,891
SCNN1A	1,300

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCNN1A	P37088	3
LTBR	P36941	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Sensory perception of salty taste	1	951.7×	0.008	SCNN1A
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway	1	335.9×	0.012	LTBR
Sensory perception of taste	1	167.9×	0.016	SCNN1A
TNFR2 non-canonical NF-kB pathway	1	90.6×	0.022	LTBR
Stimuli-sensing channels	1	68.0×	0.023	SCNN1A
Ion channel transport	1	48.0×	0.024	SCNN1A
Sensory Perception	1	47.6×	0.024	SCNN1A
Transport of small molecules	1	12.6×	0.078	SCNN1A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
hematopoietic or lymphoid organ development	1	8426.0×	0.002	LTBR
sensory perception of salty taste	1	2106.5×	0.004	SCNN1A
cellular response to aldosterone	1	1203.7×	0.004	SCNN1A
cellular response to vasopressin	1	1053.2×	0.004	SCNN1A
multicellular organismal-level water homeostasis	1	842.6×	0.004	SCNN1A
sensory perception of sour taste	1	842.6×	0.004	SCNN1A
myeloid dendritic cell differentiation	1	468.1×	0.005	LTBR
sodium ion homeostasis	1	468.1×	0.005	SCNN1A
intracellular sodium ion homeostasis	1	383.0×	0.005	SCNN1A
cellular response to acidic pH	1	366.4×	0.005	SCNN1A
sodium ion import across plasma membrane	1	312.1×	0.006	SCNN1A
positive regulation of extrinsic apoptotic signaling pathway	1	227.7×	0.007	LTBR
regulation of blood pressure	1	110.9×	0.013	SCNN1A
cellular response to mechanical stimulus	1	108.0×	0.013	LTBR
sodium ion transmembrane transport	1	101.5×	0.013	SCNN1A
positive regulation of JNK cascade	1	81.8×	0.015	LTBR
positive regulation of canonical NF-kappaB signal transduction	1	36.3×	0.032	LTBR
immune response	1	23.5×	0.047	LTBR
apoptotic process	1	14.3×	0.072	LTBR
signal transduction	1	8.0×	0.121	LTBR

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
SCNN1A	AMILORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCNN1A	2	4
LTBR	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMILORIDE	4	SCNN1A
552-02 FREE BASE	2	SCNN1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SCNN1A	6	Binding:4, ADMET:1, Functional:1
LTBR	1	Binding:1

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

2 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)
AMILORIDE	4	SCNN1A
552-02 FREE BASE	2	SCNN1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SCNN1A
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	1	LTBR

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)
LTBR	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.