familial hyperaldosteronism type III

Summary

familial hyperaldosteronism type III (MONDO:0013359) is a disease caused by KCNJ5 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KCNJ5 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 154
• Phenotypes (HPO): 17

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0000822	Hypertension	Obligate (100%)
HP:0040084	Abnormal circulating renin	Obligate (100%)
HP:0002900	Hypokalemia	Very frequent (80-99%)
HP:0008221	Adrenal hyperplasia	Very frequent (80-99%)
HP:0011740	Glucocortocoid-insensitive primary hyperaldosteronism	Very frequent (80-99%)
HP:0000360	Tinnitus	Occasional (5-29%)
HP:0000421	Epistaxis	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0001657	Prolonged QT interval	Occasional (5-29%)
HP:0001712	Left ventricular hypertrophy	Occasional (5-29%)
HP:0001959	Polydipsia	Occasional (5-29%)
HP:0002018	Nausea	Occasional (5-29%)
HP:0002150	Hypercalciuria	Occasional (5-29%)
HP:0002170	Intracranial hemorrhage	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0200114	Metabolic alkalosis	Occasional (5-29%)
HP:0011739	Dexamethasone-suppresible primary hyperaldosteronism	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hyperaldosteronism type III
Mondo ID	MONDO:0013359
OMIM	613677
Orphanet	251274
DOID	DOID:0061248
SNOMED CT	703234002
UMLS	C3838758
MedGen	824604
GARD	0012362
Is cancer (heuristic)	no

Also known as: familial hyperaldosteronism type 3 · FH III · FH-III · FH3 · HALD3

Data availability: 154 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › adrenal gland disorder › adrenal cortex disorder › adrenal gland hyperfunction › hyperaldosteronism › primary aldosteronism › familial hyperaldosteronism › familial hyperaldosteronism type III

Related subtypes (4): glucocorticoid-remediable aldosteronism, familial hyperaldosteronism type II, aldosterone-producing adenoma with seizures and neurological abnormalities, hyperaldosteronism, familial, type IV

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

154 retrieved; paginated sample, class counts are floors:

85 uncertain significance, 23 benign, 15 conflicting classifications of pathogenicity, 15 benign/likely benign, 11 likely benign, 5 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
135679	NM_000890.5(KCNJ5):c.452G>A (p.Gly151Glu)	KCNJ5	Pathogenic	criteria provided, single submitter
135680	NM_000890.5(KCNJ5):c.470T>G (p.Ile157Ser)	KCNJ5	Pathogenic	no assertion criteria provided
135681	NM_000890.5(KCNJ5):c.736G>A (p.Glu246Lys)	KCNJ5	Pathogenic	no assertion criteria provided
30125	NM_000890.5(KCNJ5):c.472A>G (p.Thr158Ala)	KCNJ5	Pathogenic	no assertion criteria provided
91915	NM_000890.5(KCNJ5):c.451G>A (p.Gly151Arg)	KCNJ5	Pathogenic	criteria provided, multiple submitters, no conflicts
1010966	NM_000890.5(KCNJ5):c.119C>T (p.Thr40Met)	KCNJ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1761254	NM_000890.5(KCNJ5):c.1253C>T (p.Ser418Leu)	KCNJ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
238195	NM_000890.5(KCNJ5):c.1124G>A (p.Arg375Gln)	KCNJ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2856410	NM_000890.5(KCNJ5):c.659G>A (p.Arg220Gln)	KCNJ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
303601	NM_000890.5(KCNJ5):c.-295C>G	KCNJ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
303610	NM_000890.5(KCNJ5):c.-293C>G	KCNJ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
303628	NM_000890.5(KCNJ5):c.430A>G (p.Ile144Val)	KCNJ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3599191	NM_000890.5(KCNJ5):c.91G>A (p.Asp31Asn)	KCNJ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
432222	NM_000890.5(KCNJ5):c.439G>A (p.Glu147Lys)	KCNJ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
843194	NM_000890.5(KCNJ5):c.1220A>G (p.Lys407Arg)	KCNJ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
878220	NM_000890.5(KCNJ5):c.-303C>G	KCNJ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
878221	NM_000890.5(KCNJ5):c.-301C>G	KCNJ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
878222	NM_000890.5(KCNJ5):c.-299C>G	KCNJ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
878223	NM_000890.5(KCNJ5):c.-297C>G	KCNJ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
941579	NM_000890.5(KCNJ5):c.214C>T (p.Arg72Trp)	KCNJ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1007137	NM_000890.5(KCNJ5):c.155G>A (p.Arg52His)	KCNJ5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1014195	NM_000890.5(KCNJ5):c.148C>T (p.Arg50Cys)	KCNJ5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1019977	NM_000890.5(KCNJ5):c.902T>A (p.Val301Asp)	KCNJ5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1040985	NM_000890.5(KCNJ5):c.274G>A (p.Val92Ile)	KCNJ5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1045677	NM_000890.5(KCNJ5):c.532G>A (p.Val178Ile)	KCNJ5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1050347	NM_000890.5(KCNJ5):c.1248G>C (p.Arg416Ser)	KCNJ5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1054696	NM_000890.5(KCNJ5):c.994C>T (p.Arg332Ter)	KCNJ5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1058806	NM_000890.5(KCNJ5):c.631C>T (p.Arg211Trp)	KCNJ5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1306130	NM_000890.5(KCNJ5):c.704G>A (p.Arg235Gln)	KCNJ5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1326808	NM_000890.5(KCNJ5):c.955C>T (p.Arg319Trp)	KCNJ5	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
KCNJ5	Definitive	Autosomal dominant	familial hyperaldosteronism type III	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNJ5	Orphanet:101016	Romano-Ward syndrome
KCNJ5	Orphanet:251274	Familial hyperaldosteronism type III
KCNJ5	Orphanet:334	Hereditary atrial fibrillation
KCNJ5	Orphanet:37553	Andersen-Tawil syndrome

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
KCNJ5	HGNC:6266	ENSG00000120457	P48544	G protein-activated inward rectifier potassium channel 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNJ5	G protein-activated inward rectifier potassium channel 4	Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it.

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
Ion channel	1	111.5×	0.009

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNJ5	Ion channel	yes		K_chnl_inward-rec_Kir3.4, K_chnl_inward-rec_Kir_cyto, Ig_E-set

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
adrenal cortex	1
buccal mucosa cell	1
endothelial cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNJ5	175	broad	marker	buccal mucosa cell, endothelial cell, adrenal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNJ5	1,147

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KCNJ5	P48544	82.01

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
G protein gated Potassium channels	1	1142.0×	0.005	KCNJ5
Inwardly rectifying K+ channels	1	713.8×	0.005	KCNJ5
Activation of GABAB receptors	1	601.0×	0.005	KCNJ5
GABA B receptor activation	1	543.8×	0.005	KCNJ5
Activation of G protein gated Potassium channels	1	393.8×	0.005	KCNJ5
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits	1	393.8×	0.005	KCNJ5
GABA receptor activation	1	317.2×	0.005	KCNJ5
Potassium Channels	1	134.3×	0.010	KCNJ5
Neurotransmitter receptors and postsynaptic signal transmission	1	100.2×	0.012	KCNJ5
Transmission across Chemical Synapses	1	76.1×	0.014	KCNJ5
Neuronal System	1	44.3×	0.023	KCNJ5

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
ventricular cardiac muscle cell membrane repolarization	1	5617.3×	0.001	KCNJ5
membrane repolarization during atrial cardiac muscle cell action potential	1	2808.7×	0.001	KCNJ5
regulation of monoatomic ion transmembrane transport	1	732.7×	0.003	KCNJ5
regulation of heart rate by cardiac conduction	1	374.5×	0.004	KCNJ5
potassium ion import across plasma membrane	1	366.4×	0.004	KCNJ5
potassium ion transport	1	191.5×	0.006	KCNJ5
potassium ion transmembrane transport	1	135.9×	0.007	KCNJ5

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNJ5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNJ5	32	Binding:32

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

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	0
D	Druggable family + AlphaFold only, no drug	1	KCNJ5
E	Difficult family or no structure, no drug	0

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)
KCNJ5	32	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.