Bartter disease type 4B

Summary

Bartter disease type 4B (MONDO:0000909) is a disease caused by CLCNKB (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: CLCNKB (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 227

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Bartter disease type 4B
Mondo ID	MONDO:0000909
OMIM	613090
DOID	DOID:0110146
UMLS	C4310805
MedGen	934772
GARD	0015612
Is cancer (heuristic)	no

Also known as: BARTS4B · Bartter disease type 4B · Bartter syndrome, type 4B

Data availability: 227 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Bartter syndrome › Bartter syndrome type 4 › Bartter disease type 4B

Related subtypes (1): Bartter disease type 4A

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

227 retrieved; paginated sample, class counts are floors:

105 uncertain significance, 34 benign, 21 conflicting classifications of pathogenicity, 18 likely pathogenic, 15 pathogenic, 13 likely benign, 11 pathogenic/likely pathogenic, 10 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
7589	NM_004070.4(CLCNKA):c.240G>C (p.Trp80Cys)	CLCNKA	Pathogenic	no assertion criteria provided
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
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
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
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
975076	NM_000085.5(CLCNKB):c.226C>T (p.Arg76Ter)	CLCNKB	Pathogenic	criteria provided, multiple submitters, no conflicts
7590	NM_004070.4(CLCNKA):c.778C>T (p.Gln260Ter)	LOC106501712	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
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
7592	NM_000085.5(CLCNKB):c.610G>A (p.Ala204Thr)	LOC106501713	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7593	NM_000085.5(CLCNKB):c.1312C>T (p.Arg438Cys)	LOC106501713	Pathogenic	criteria provided, multiple submitters, no conflicts
7597	NM_000085.5(CLCNKB):c.782-2A>G	LOC106501713	Pathogenic	criteria provided, multiple submitters, no conflicts
7599	NM_000085.5(CLCNKB):c.1830G>A (p.Trp610Ter)	LOC106501713	Pathogenic	criteria provided, multiple submitters, no conflicts
804713	NM_000085.5(CLCNKB):c.1325A>G (p.Glu442Gly)	LOC106501713	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2582354	NM_004070.4(CLCNKA):c.1885G>T (p.Glu629Ter)	CLCNKA	Likely pathogenic	criteria provided, single submitter
3599296	NM_000085.5(CLCNKB):c.781G>T (p.Glu261Ter)	CLCNKB	Likely pathogenic	criteria provided, single submitter
3599306	NM_000085.5(CLCNKB):c.846CTT[1] (p.Phe285del)	CLCNKB	Likely pathogenic	criteria provided, single submitter
3599313	NM_000085.5(CLCNKB):c.869del	CLCNKB	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 7 · 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
CLCNKA	Moderate	Unknown	Bartter disease type 4B	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLCNKA	Orphanet:89938	Bartter syndrome type 4
CLCNKB	Orphanet:358	Gitelman syndrome
CLCNKB	Orphanet:89938	Bartter syndrome type 4
CLCNKB	Orphanet:93605	Bartter syndrome type 3
COL12A1	Orphanet:536516	Myopathic Ehlers-Danlos syndrome
COL12A1	Orphanet:610	Bethlem muscular dystrophy
COL12A1	Orphanet:75840	Ullrich congenital muscular dystrophy

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
CLCNKA	HGNC:2026	ENSG00000186510	P51800	Chloride channel protein ClC-Ka	gencc,clinvar
CLCNKB	HGNC:2027	ENSG00000184908	P51801	Chloride channel protein ClC-Kb	gencc,clinvar
COL12A1	HGNC:2188	ENSG00000111799	Q99715	Collagen alpha-1(XII) chain	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLCNKA	Chloride channel protein ClC-Ka	Anion-selective channel permeable to small monovalent anions with ion selectivity for chloride > bromide > nitrate > iodide.
CLCNKB	Chloride channel protein ClC-Kb	Anion-selective channel permeable to small monovalent anions with ion selectivity for chloride > bromide > nitrate > iodide.
COL12A1	Collagen alpha-1(XII) chain	Type XII collagen interacts with type I collagen-containing fibrils, the COL1 domain could be associated with the surface of the fibrils, and the COL2 and NC3 domains may be localized in the perifibrillar matrix.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Antibody/Immunoglobulin	1	9.7×	0.199
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CLCNKA	Other/Unknown	no		CBS_dom, ClC, Cl_channel-K
CLCNKB	Other/Unknown	no		CBS_dom, ClC, Cl_channel-K
COL12A1	Antibody/Immunoglobulin	yes		VWF_A, FN3_dom, Collagen

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
adult mammalian kidney	2
metanephros cortex	2
left lobe of thyroid gland	1
renal medulla	1
calcaneal tendon	1
cartilage tissue	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLCNKA	130	tissue_specific	marker	metanephros cortex, adult mammalian kidney, left lobe of thyroid gland
CLCNKB	165	broad	marker	renal medulla, adult mammalian kidney, metanephros cortex
COL12A1	240	ubiquitous	marker	tibia, calcaneal tendon, cartilage tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL12A1	2,219
CLCNKB	767
CLCNKA	724

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLCNKA	P51800	1
COL12A1	Q99715	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLCNKB	P51801	87.16

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Stimuli-sensing channels	2	90.6×	8e-04	CLCNKA, CLCNKB
Collagen chain trimerization	1	86.5×	0.017	COL12A1
Assembly of collagen fibrils and other multimeric structures	1	66.8×	0.017	COL12A1
Collagen degradation	1	58.6×	0.017	COL12A1
Collagen biosynthesis and modifying enzymes	1	56.8×	0.017	COL12A1

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
transepithelial chloride transport	2	1248.3×	3e-06	CLCNKA, CLCNKB
renal absorption	2	1123.5×	3e-06	CLCNKA, CLCNKB
chloride transport	2	303.6×	3e-05	CLCNKA, CLCNKB
renal sodium ion absorption	1	330.4×	0.005	CLCNKB
endodermal cell differentiation	1	165.2×	0.008	COL12A1
collagen fibril organization	1	74.9×	0.016	COL12A1
cell adhesion	1	12.5×	0.078	COL12A1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
CLCNKA	0	0
CLCNKB	0	0
COL12A1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	1	COL12A1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CLCNKA, CLCNKB

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CLCNKA	0	—
CLCNKB	0	—
COL12A1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.