Bartter disease type 3

Summary

Bartter disease type 3 (MONDO:0011822) is a disease caused by CLCNKB (GenCC Strong), with 5 cohort genes.

At a glance

• Prevalence: Unknown (Europe) [Orphanet-validated]
• Causal gene: CLCNKB (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 237

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Bartter disease type 3
Mondo ID	MONDO:0011822
OMIM	607364
Orphanet	93605
DOID	DOID:0110144
SNOMED CT	700111000
UMLS	C1846343
MedGen	335399
GARD	0009659
Is cancer (heuristic)	no

Also known as: adult Bartter syndrome · BARTS3 · Bartter disease type 3 · Bartter syndrome classic · Bartter syndrome type 3 · Bartter syndrome type III

Data availability: 237 ClinVar variants · 2 GenCC gene-disease records · 1 cell line.

Disease family

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

Related subtypes (5): Bartter disease type 2, Bartter disease type 5, Bartter syndrome with hypocalcemia, Bartter syndrome type 4, Bartter disease type 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

237 retrieved; paginated sample, class counts are floors:

108 uncertain significance, 26 pathogenic, 25 benign, 25 likely pathogenic, 19 conflicting classifications of pathogenicity, 13 likely benign, 12 pathogenic/likely pathogenic, 9 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1179108	GRCh37/hg19 1p36.13(chr1:16370960-16383841)	CLCNKB	Pathogenic	no assertion criteria provided
1285112	NM_000085.5(CLCNKB):c.968+1G>A	CLCNKB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322094	NM_000085.5(CLCNKB):c.508G>A (p.Val170Met)	CLCNKB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1805279	NM_000085.5(CLCNKB):c.619del (p.Val207fs)	CLCNKB	Pathogenic	criteria provided, multiple submitters, no conflicts
2055600	NM_000085.5(CLCNKB):c.1313G>A (p.Arg438His)	CLCNKB	Pathogenic	criteria provided, multiple submitters, no conflicts
3340600	NM_000085.5(CLCNKB):c.36del (p.Asn14fs)	CLCNKB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
447098	NM_000085.5(CLCNKB):c.1783C>T (p.Arg595Ter)	CLCNKB	Pathogenic	criteria provided, multiple submitters, no conflicts
447106	NM_000085.5(CLCNKB):c.73del (p.Cys25fs)	CLCNKB	Pathogenic	criteria provided, multiple submitters, no conflicts
523321	NM_000085.5(CLCNKB):c.937_940dup (p.Arg314delinsLysTer)	CLCNKB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
585704	NM_000085.5(CLCNKB):c.18dup (p.Leu7fs)	CLCNKB	Pathogenic	criteria provided, multiple submitters, no conflicts
638509	NM_000085.5(CLCNKB):c.1476del (p.Gly493fs)	CLCNKB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7595	NM_000085.5(CLCNKB):c.1294T>C (p.Tyr432His)	CLCNKB	Pathogenic	no assertion criteria provided
7596	NC_000001.11:g.(?16043782)(16057326_?)del	CLCNKB	Pathogenic	no assertion criteria provided
801446	NM_000085.5(CLCNKB):c.673G>T (p.Glu225Ter)	CLCNKB	Pathogenic	criteria provided, multiple submitters, no conflicts
801447	NM_000085.5(CLCNKB):c.708C>A (p.Tyr236Ter)	CLCNKB	Pathogenic	criteria provided, multiple submitters, no conflicts
801448	NM_000085.5(CLCNKB):c.910C>T (p.Arg304Ter)	CLCNKB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
801449	NM_000085.5(CLCNKB):c.1309G>A (p.Gly437Arg)	CLCNKB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
930786	NM_000085.5(CLCNKB):c.1389del (p.Tyr466fs)	CLCNKB	Pathogenic	criteria provided, multiple submitters, no conflicts
974551	NM_000085.5:c.(?-1)(*1_?)del	CLCNKB	Pathogenic	criteria provided, single submitter
975076	NM_000085.5(CLCNKB):c.226C>T (p.Arg76Ter)	CLCNKB	Pathogenic	criteria provided, multiple submitters, no conflicts
915980	GRCh37/hg19 1p36.13(chr1:16372179-16388605)	FAM131C	Pathogenic	no assertion criteria provided
1179088	NM_000085.5(CLCNKB):c.274C>T (p.Arg92Trp)	LOC106501713	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456684	NM_000085.5(CLCNKB):c.1051C>T (p.Arg351Trp)	LOC106501713	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
216904	NM_000085.5(CLCNKB):c.1897del (p.Thr632_Leu633insTer)	LOC106501713	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235350	NM_000085.5(CLCNKB):c.1693del (p.Glu565fs)	LOC106501713	Pathogenic	criteria provided, multiple submitters, no conflicts
2446052	Single allele	LOC106501713	Pathogenic	criteria provided, single submitter
3381876	NM_000085.5(CLCNKB):c.835del (p.Leu279fs)	LOC106501713	Pathogenic	criteria provided, single submitter
3599427	NM_000085.5(CLCNKB):c.1228-2A>G	LOC106501713	Pathogenic	criteria provided, single submitter
369968	NM_000085.5(CLCNKB):c.1381dup (p.Ile461fs)	LOC106501713	Pathogenic	no assertion criteria provided
3775672	NM_000085.5(CLCNKB):c.1614del (p.Asn539fs)	LOC106501713	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
CLCNKB	Strong	Autosomal recessive	Bartter disease type 3	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLCNKB	Orphanet:358	Gitelman syndrome
CLCNKB	Orphanet:89938	Bartter syndrome type 4
CLCNKB	Orphanet:93605	Bartter syndrome type 3
CASR	Orphanet:417	Neonatal severe primary hyperparathyroidism
CASR	Orphanet:428	Autosomal dominant hypocalcemia
CASR	Orphanet:676	Autosomal dominant hereditary chronic pancreatitis
CASR	Orphanet:93372	Familial hypocalciuric hypercalcemia type 1
CLCNKA	Orphanet:89938	Bartter syndrome type 4

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CLCNKB	HGNC:2027	ENSG00000184908	P51801	Chloride channel protein ClC-Kb	gencc,clinvar
SLC12A1	HGNC:10910	ENSG00000074803	Q13621	Solute carrier family 12 member 1	clinvar
CASR	HGNC:1514	ENSG00000036828	P41180	Extracellular calcium-sensing receptor	clinvar
CLCNKA	HGNC:2026	ENSG00000186510	P51800	Chloride channel protein ClC-Ka	clinvar
FAM131C	HGNC:26717	ENSG00000185519	Q96AQ9	Protein FAM131C	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLCNKB	Chloride channel protein ClC-Kb	Anion-selective channel permeable to small monovalent anions with ion selectivity for chloride > bromide > nitrate > iodide.
SLC12A1	Solute carrier family 12 member 1	Renal sodium, potassium and chloride non-electrogenic ion symporter that mediates the transepithelial NaCl reabsorption in the thick ascending limb and plays an essential role in the urinary concentration and volume regulation.
CASR	Extracellular calcium-sensing receptor	G-protein-coupled receptor that senses changes in the extracellular concentration of calcium ions and plays a key role in maintaining calcium homeostasis.
CLCNKA	Chloride channel protein ClC-Ka	Anion-selective channel permeable to small monovalent anions with ion selectivity for chloride > bromide > nitrate > iodide.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.2

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
GPCR	1	4.8×	0.269
Other/Unknown	4	1.4×	0.269

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CLCNKB	Other/Unknown	no		CBS_dom, ClC, Cl_channel-K
SLC12A1	Other/Unknown	no		SLC12A1/SLC12A2, Slc12a1, AA-permease/SLC12A_dom
CASR	GPCR	yes		GPCR_3_Ca_sens_rcpt-rel, GPCR_3, ANF_lig-bd_rcpt
CLCNKA	Other/Unknown	no		CBS_dom, ClC, Cl_channel-K
FAM131C	Other/Unknown	no		FAM131

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephros cortex	3
adult mammalian kidney	2
renal medulla	2
nephron tubule	1
diaphragm	1
hair follicle	1
islet of Langerhans	1
left lobe of thyroid gland	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLCNKB	165	broad	marker	renal medulla, adult mammalian kidney, metanephros cortex
SLC12A1	185	tissue_specific	marker	renal medulla, nephron tubule, metanephros cortex
CASR	63	tissue_specific	marker	islet of Langerhans, diaphragm, hair follicle
CLCNKA	130	tissue_specific	marker	metanephros cortex, adult mammalian kidney, left lobe of thyroid gland
FAM131C	116	broad	marker	cerebellar cortex, cerebellar hemisphere, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CASR	2,692
SLC12A1	1,448
CLCNKB	767
CLCNKA	724
FAM131C	375

Intra-cohort edges

A	B	Sources
CASR	CLCNKB	string_interaction
CASR	SLC12A1	string_interaction
CLCNKA	SLC12A1	string_interaction
CLCNKB	SLC12A1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CASR	P41180	31
CLCNKA	P51800	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLCNKB	P51801	87.16
SLC12A1	Q13621	78.39
FAM131C	Q96AQ9	58.40

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC12A1 causes Bartter syndrome 1 (BS1)	1	2855.0×	0.003	SLC12A1
Stimuli-sensing channels	2	68.0×	0.003	CLCNKB, CLCNKA
Cation-coupled Chloride cotransporters	1	407.9×	0.013	SLC12A1
Class C/3 (Metabotropic glutamate/pheromone receptors)	1	73.2×	0.054	CASR
SLC transporter disorders	1	51.0×	0.062	SLC12A1
Disorders of transmembrane transporters	1	34.8×	0.070	SLC12A1
R-HSA-425393	1	32.4×	0.070	SLC12A1
GPCR ligand binding	1	16.0×	0.109	CASR
SLC-mediated transmembrane transport	1	14.8×	0.109	SLC12A1
G alpha (q) signalling events	1	14.3×	0.109	CASR
GPCR downstream signalling	1	10.9×	0.122	CASR
Signaling by GPCR	1	10.0×	0.122	CASR
G alpha (i) signalling events	1	9.7×	0.122	CASR
Transport of small molecules	1	6.3×	0.171	SLC12A1
Disease	1	3.3×	0.291	SLC12A1
Signal Transduction	1	2.5×	0.339	CASR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
transepithelial chloride transport	2	936.2×	4e-05	CLCNKB, CLCNKA
renal absorption	2	842.6×	4e-05	CLCNKB, CLCNKA
chloride transport	2	227.7×	4e-04	CLCNKB, CLCNKA
chloride transmembrane transport	2	118.7×	0.001	SLC12A1, CASR
regulation of presynaptic membrane potential	1	2106.5×	0.004	CASR
chemosensory behavior	1	842.6×	0.007	CASR
bile acid secretion	1	842.6×	0.007	CASR
transepithelial ammonium transport	1	842.6×	0.007	SLC12A1
ammonium homeostasis	1	601.9×	0.008	SLC12A1
response to fibroblast growth factor	1	526.6×	0.009	CASR
fat pad development	1	421.3×	0.009	CASR
cellular response to peptide	1	421.3×	0.009	CASR
chloride ion homeostasis	1	383.0×	0.009	SLC12A1
cellular response to vitamin D	1	383.0×	0.009	CASR
positive regulation of positive chemotaxis	1	351.1×	0.009	CASR
detection of calcium ion	1	280.9×	0.010	CASR
cellular response to hepatocyte growth factor stimulus	1	280.9×	0.010	CASR
renal sodium ion absorption	1	247.8×	0.010	CLCNKB
sodium ion homeostasis	1	234.1×	0.010	SLC12A1
positive regulation of calcium ion import	1	234.1×	0.010	CASR
cellular response to low-density lipoprotein particle stimulus	1	221.7×	0.010	CASR
regulation of calcium ion transport	1	200.6×	0.010	CASR
potassium ion homeostasis	1	191.5×	0.010	SLC12A1
branching morphogenesis of an epithelial tube	1	183.2×	0.010	CASR
cell volume homeostasis	1	150.5×	0.012	SLC12A1
positive regulation of vasoconstriction	1	150.5×	0.012	CASR
positive regulation of NLRP3 inflammasome complex assembly	1	145.3×	0.012	CASR
vasodilation	1	91.6×	0.017	CASR
potassium ion import across plasma membrane	1	91.6×	0.017	SLC12A1
JNK cascade	1	68.0×	0.022	CASR

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) 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
CASR	CINACALCET HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CASR	10	4
CLCNKB	0	0
SLC12A1	0	0
CLCNKA	0	0
FAM131C	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CINACALCET HYDROCHLORIDE	4	CASR
CINACALCET	4	CASR
ENCALERET	3	CASR
EVOCALCET	3	CASR
SB-423562	2	CASR
RONACALERET	2	CASR
TECALCET HYDROCHLORIDE	2	CASR
FENDILINE	2	CASR
TECALCET	2	CASR
ATF-936	1	CASR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CASR	45	Functional:32, Binding:13

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

10 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)
CINACALCET HYDROCHLORIDE	4	CASR
CINACALCET	4	CASR
ENCALERET	3	CASR
EVOCALCET	3	CASR
SB-423562	2	CASR
RONACALERET	2	CASR
TECALCET HYDROCHLORIDE	2	CASR
FENDILINE	2	CASR
TECALCET	2	CASR
ATF-936	1	CASR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CASR
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	4	CLCNKB, SLC12A1, CLCNKA, FAM131C

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CLCNKB	0	—
SLC12A1	0	—
CLCNKA	0	—
FAM131C	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.