Bronchiectasis with or without elevated sweat chloride 2

Summary

Bronchiectasis with or without elevated sweat chloride 2 (MONDO:0013087) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 210

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	bronchiectasis with or without elevated sweat chloride 2
Mondo ID	MONDO:0013087
MeSH	C567813
OMIM	613021
DOID	DOID:0080527
UMLS	C2751666
MedGen	414437
GARD	0018055
Is cancer (heuristic)	no

Also known as: BESC2 · bronchiectasis caused by mutation in SCNN1A · bronchiectasis with or without elevated sweat chloride 2 · bronchiectasis with or without elevated sweat chloride type 2 · SCNN1A bronchiectasis

Data availability: 210 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › lower respiratory tract disorder › bronchial disorder › bronchiectasis › idiopathic bronchiectasis › bronchiectasis with or without elevated sweat chloride 2

Related subtypes (2): bronchiectasis with or without elevated sweat chloride 1, bronchiectasis with or without elevated sweat chloride 3

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

210 retrieved; paginated sample, class counts are floors:

135 uncertain significance, 36 conflicting classifications of pathogenicity, 14 benign/likely benign, 7 benign, 6 pathogenic, 6 likely pathogenic, 4 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
9270	NM_001038.6(SCNN1A):c.241C>T (p.Arg81Cys)	SCNN1A	Pathogenic	no assertion criteria provided
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
4277949	NM_001038.6(SCNN1A):c.19del (p.Glu7fs)	SCNN1A	Likely pathogenic	criteria provided, single submitter
591450	NM_001038.6(SCNN1A):c.69del (p.Asn24fs)	SCNN1A	Likely pathogenic	criteria provided, single submitter
591722	NM_001038.6(SCNN1A):c.-55+2T>C	LTBR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
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
310119	NM_001038.6(SCNN1A):c.*914A>G	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310126	NM_001038.6(SCNN1A):c.*296C>T	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310128	NM_001038.6(SCNN1A):c.*113C>T	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310131	NM_001038.6(SCNN1A):c.1935C>T (p.Ala645=)	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310132	NM_001038.6(SCNN1A):c.1766G>A (p.Arg589Gln)	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310133	NM_001038.6(SCNN1A):c.1686G>A (p.Ser562=)	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
310135	NM_001038.6(SCNN1A):c.1554-6C>T	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310136	NM_001038.6(SCNN1A):c.1497+6G>C	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310137	NM_001038.6(SCNN1A):c.1485G>T (p.Ser495=)	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310138	NM_001038.6(SCNN1A):c.1484C>T (p.Ser495Leu)	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310139	NM_001038.6(SCNN1A):c.1299C>T (p.Tyr433=)	SCNN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 8 · 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	Moderate	Autosomal dominant	bronchiectasis with or without elevated sweat chloride 2	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
SLC34A1	Orphanet:157215	Hereditary hypophosphatemic rickets with hypercalciuria
SLC34A1	Orphanet:244305	Dominant hypophosphatemia with nephrolithiasis or osteoporosis
SLC34A1	Orphanet:300547	Autosomal recessive infantile hypercalcemia
SLC34A1	Orphanet:3337	Primary Fanconi renotubular syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCNN1A	HGNC:10599	ENSG00000111319	P37088	Epithelial sodium channel subunit alpha	gencc,clinvar
SLC34A1	HGNC:11019	ENSG00000131183	Q06495	Sodium-dependent phosphate transport protein 2A	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.
SLC34A1	Sodium-dependent phosphate transport protein 2A	Involved in actively transporting phosphate into cells via Na(+) cotransport in the renal brush border membrane.
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: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCNN1A	Other/Unknown	no		ENaC, ENaC_chordates, ENaC_CS
SLC34A1	Other/Unknown	no		Na/Pi_transpt
LTBR	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_3_LTBR, TNFRSF3_N

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephros cortex	1
nasal cavity epithelium	1
right uterine tube	1
adult mammalian kidney	1
kidney epithelium	1
nephron tubule	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
SLC34A1	52	tissue_specific	marker	nephron tubule, adult mammalian kidney, kidney epithelium
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
SLC34A1	3,362
LTBR	1,891
SCNN1A	1,300

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCNN1A	P37088	3
LTBR	P36941	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC34A1	Q06495	72.24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC34A1 causes hypophosphatemic nephrolithiasis/osteoporosis 1 (NPHLOP1)	1	1903.3×	0.006	SLC34A1
Type II Na+/Pi cotransporters	1	951.7×	0.006	SLC34A1
Sensory perception of salty taste	1	634.4×	0.006	SCNN1A
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway	1	223.9×	0.012	LTBR
Surfactant metabolism	1	122.8×	0.016	SLC34A1
Sensory perception of taste	1	112.0×	0.016	SCNN1A
TNFR2 non-canonical NF-kB pathway	1	60.4×	0.026	LTBR
Stimuli-sensing channels	1	45.3×	0.030	SCNN1A
Ion channel transport	1	32.0×	0.034	SCNN1A
Sensory Perception	1	31.7×	0.034	SCNN1A
Transport of small molecules	1	8.4×	0.115	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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sodium ion import across plasma membrane	2	416.1×	4e-04	SCNN1A, SLC34A1
hematopoietic or lymphoid organ development	1	5617.3×	0.003	LTBR
indole metabolic process	1	2808.7×	0.003	SLC34A1
gentamycin metabolic process	1	2808.7×	0.003	SLC34A1
arsenate ion transmembrane transport	1	2808.7×	0.003	SLC34A1
positive regulation of phosphate transmembrane transport	1	2808.7×	0.003	SLC34A1
cellular response to phosphate starvation	1	1404.3×	0.004	SLC34A1
sensory perception of salty taste	1	1404.3×	0.004	SCNN1A
cellular response to metal ion	1	1404.3×	0.004	SLC34A1
positive regulation of sodium-dependent phosphate transport	1	1404.3×	0.004	SLC34A1
cellular response to staurosporine	1	1123.5×	0.004	SLC34A1
positive regulation of membrane potential	1	936.2×	0.004	SLC34A1
tricarboxylic acid metabolic process	1	936.2×	0.004	SLC34A1
response to mercury ion	1	802.5×	0.004	SLC34A1
cellular response to aldosterone	1	802.5×	0.004	SCNN1A
response to potassium ion	1	702.2×	0.004	SLC34A1
response to thyroid hormone	1	702.2×	0.004	SLC34A1
dentinogenesis	1	702.2×	0.004	SLC34A1
cellular response to vasopressin	1	702.2×	0.004	SCNN1A
phosphate ion transport	1	624.1×	0.004	SLC34A1
sodium-dependent phosphate transport	1	624.1×	0.004	SLC34A1
multicellular organismal-level water homeostasis	1	561.7×	0.004	SCNN1A
sensory perception of sour taste	1	561.7×	0.004	SCNN1A
intracellular phosphate ion homeostasis	1	510.7×	0.004	SLC34A1
response to magnesium ion	1	468.1×	0.004	SLC34A1
cellular response to parathyroid hormone stimulus	1	468.1×	0.004	SLC34A1
phosphate ion transmembrane transport	1	401.2×	0.005	SLC34A1
glycoprotein metabolic process	1	374.5×	0.005	SLC34A1
response to growth hormone	1	374.5×	0.005	SLC34A1
response to peptide	1	374.5×	0.005	SLC34A1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 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
SLC34A1	SODIUM PHOSPHATE, DIBASIC, ANHYDROUS

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCNN1A	2	4
SLC34A1	2	4
LTBR	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMILORIDE	4	SCNN1A
SODIUM PHOSPHATE, DIBASIC, ANHYDROUS	4	SLC34A1
POTASSIUM PHOSPHATE, MONOBASIC	4	SLC34A1
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
SLC34A1	8	Binding:7, Functional:1
SCNN1A	6	Binding:4, ADMET:1, Functional:1
LTBR	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

4 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
SODIUM PHOSPHATE, DIBASIC, ANHYDROUS	4	SLC34A1
POTASSIUM PHOSPHATE, MONOBASIC	4	SLC34A1
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)	2	SCNN1A, SLC34A1
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.