Bartter syndrome with hypocalcemia

Summary

Bartter syndrome with hypocalcemia (MONDO:0016983) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Bartter syndrome with hypocalcemia
Mondo ID	MONDO:0016983
Orphanet	263417
UMLS	C4552089
MedGen	1645787
GARD	0025084
Is cancer (heuristic)	no

Also known as: Bartter syndrome type 5 · Bartter syndrome type V

Data availability: 8 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Bartter syndrome › Bartter syndrome with hypocalcemia

Related subtypes (5): Bartter disease type 2, Bartter disease type 5, Bartter disease type 3, 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

8 retrieved; paginated sample, class counts are floors:

2 pathogenic, 2 uncertain significance, 2 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1177515	NM_000388.4(CASR):c.209G>A (p.Trp70Ter)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts
60669	NM_000388.4(CASR):c.85A>G (p.Lys29Glu)	CASR	Pathogenic	no assertion criteria provided
8346	NM_000388.4(CASR):c.374T>C (p.Leu125Pro)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8343	NM_000388.4(CASR):c.2528C>A (p.Ala843Glu)	CASR	Likely pathogenic	criteria provided, single submitter
566469	NM_000388.4(CASR):c.494T>G (p.Val165Gly)	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
652572	NM_000388.4(CASR):c.2278A>T (p.Ile760Phe)	CASR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1488458	NM_000388.4(CASR):c.2503G>C (p.Ala835Pro)	CASR	Uncertain significance	criteria provided, single submitter
8344	NM_000388.4(CASR):c.393C>G (p.Cys131Trp)	CASR	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CASR	HGNC:1514	ENSG00000036828	P41180	Extracellular calcium-sensing receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
GPCR	1	23.9×	0.042

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CASR	GPCR	yes		GPCR_3_Ca_sens_rcpt-rel, GPCR_3, ANF_lig-bd_rcpt

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
diaphragm	1
hair follicle	1
islet of Langerhans	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CASR	63	tissue_specific	marker	islet of Langerhans, diaphragm, hair follicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CASR	2,692

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CASR	P41180	31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Class C/3 (Metabotropic glutamate/pheromone receptors)	1	292.8×	0.024	CASR
GPCR ligand binding	1	64.2×	0.030	CASR
G alpha (q) signalling events	1	57.4×	0.030	CASR
GPCR downstream signalling	1	43.4×	0.030	CASR
Signaling by GPCR	1	40.1×	0.030	CASR
G alpha (i) signalling events	1	39.0×	0.030	CASR
Signal Transduction	1	10.2×	0.098	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of presynaptic membrane potential	1	8426.0×	0.003	CASR
chemosensory behavior	1	3370.4×	0.003	CASR
bile acid secretion	1	3370.4×	0.003	CASR
response to fibroblast growth factor	1	2106.5×	0.003	CASR
fat pad development	1	1685.2×	0.003	CASR
cellular response to peptide	1	1685.2×	0.003	CASR
cellular response to vitamin D	1	1532.0×	0.003	CASR
positive regulation of positive chemotaxis	1	1404.3×	0.003	CASR
detection of calcium ion	1	1123.5×	0.003	CASR
cellular response to hepatocyte growth factor stimulus	1	1123.5×	0.003	CASR
positive regulation of calcium ion import	1	936.2×	0.003	CASR
cellular response to low-density lipoprotein particle stimulus	1	887.0×	0.003	CASR
regulation of calcium ion transport	1	802.5×	0.003	CASR
branching morphogenesis of an epithelial tube	1	732.7×	0.003	CASR
positive regulation of vasoconstriction	1	601.9×	0.003	CASR
positive regulation of NLRP3 inflammasome complex assembly	1	581.1×	0.003	CASR
vasodilation	1	366.4×	0.005	CASR
JNK cascade	1	271.8×	0.006	CASR
cellular response to glucose stimulus	1	267.5×	0.006	CASR
positive regulation of insulin secretion	1	255.3×	0.006	CASR
response to ischemia	1	251.5×	0.006	CASR
chloride transmembrane transport	1	237.3×	0.006	CASR
ossification	1	227.7×	0.006	CASR
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1	218.9×	0.006	CASR
intracellular calcium ion homeostasis	1	145.3×	0.009	CASR
anatomical structure morphogenesis	1	139.3×	0.009	CASR
phospholipase C-activating G protein-coupled receptor signaling pathway	1	131.7×	0.009	CASR
cellular response to hypoxia	1	121.2×	0.009	CASR
positive regulation of ERK1 and ERK2 cascade	1	85.1×	0.013	CASR
positive regulation of gene expression	1	38.7×	0.028	CASR

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
CASR	CINACALCET HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CASR	10	4

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: 1; 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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.