Brugada syndrome 9

Summary

Brugada syndrome 9 (MONDO:0014621) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 26

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Brugada syndrome 9
Mondo ID	MONDO:0014621
OMIM	616399
DOID	DOID:0110226
UMLS	C4225340
MedGen	903155
GARD	0016104
Is cancer (heuristic)	no

Also known as: BRGDA9 · Brugada syndrome 9 · Brugada syndrome caused by mutation in KCND3 · Brugada syndrome type 9 · KCND3 Brugada syndrome

Data availability: 26 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart conduction disease › Brugada syndrome › Brugada syndrome 9

Related subtypes (8): Brugada syndrome 1, Brugada syndrome 2, Brugada syndrome 3, Brugada syndrome 4, Brugada syndrome 5, Brugada syndrome 6, Brugada syndrome 7, Brugada syndrome 8

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

26 retrieved; paginated sample, class counts are floors:

11 conflicting classifications of pathogenicity, 9 uncertain significance, 3 benign/likely benign, 2 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
192255	NM_001378969.1(KCND3):c.1174G>A (p.Val392Ile)	KCND3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1445313	NM_001378969.1(KCND3):c.1702C>T (p.Arg568Cys)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
192253	NM_001378969.1(KCND3):c.1348C>T (p.Leu450Phe)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
192254	NM_001378969.1(KCND3):c.1798G>A (p.Gly600Arg)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
383943	NM_001378969.1(KCND3):c.1111G>A (p.Gly371Arg)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
432538	NM_001378969.1(KCND3):c.1370C>T (p.Thr457Met)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
519297	NM_001378969.1(KCND3):c.1756C>G (p.Leu586Val)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
519484	NM_001378969.1(KCND3):c.1292G>A (p.Arg431His)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
586062	NM_001378969.1(KCND3):c.1027G>A (p.Glu343Lys)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
934670	NM_001378969.1(KCND3):c.1889G>A (p.Arg630Gln)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
995132	NM_001378969.1(KCND3):c.1649G>A (p.Arg550His)	KCND3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
488160	NM_001105206.3(LAMA4):c.3742A>G (p.Ile1248Val)	LAMA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1014492	NM_001378969.1(KCND3):c.1600C>A (p.Pro534Thr)	KCND3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1027158	NM_001378969.1(KCND3):c.1946T>C (p.Val649Ala)	KCND3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1057886	NM_001378969.1(KCND3):c.1864G>T (p.Ala622Ser)	KCND3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2671913	NM_001378969.1(KCND3):c.1856C>T (p.Thr619Ile)	KCND3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3382034	NM_001378969.1(KCND3):c.1227T>G (p.Ile409Met)	KCND3	Uncertain significance	criteria provided, single submitter
519471	NM_001378969.1(KCND3):c.1371G>A (p.Thr457=)	KCND3	Uncertain significance	criteria provided, multiple submitters, no conflicts
570216	NM_001378969.1(KCND3):c.1496C>G (p.Ser499Cys)	KCND3	Uncertain significance	criteria provided, multiple submitters, no conflicts
647173	NM_001378969.1(KCND3):c.1879G>A (p.Gly627Arg)	KCND3	Uncertain significance	criteria provided, multiple submitters, no conflicts
961544	NM_001378969.1(KCND3):c.346G>A (p.Asp116Asn)	KCND3	Uncertain significance	criteria provided, multiple submitters, no conflicts
240084	NM_001378969.1(KCND3):c.669G>C (p.Ser223=)	KCND3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
415284	NM_001378969.1(KCND3):c.117T>C (p.Asp39=)	KCND3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
507031	NM_001378969.1(KCND3):c.1131G>T (p.Thr377=)	KCND3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
519256	NM_001378969.1(KCND3):c.63G>C (p.Pro21=)	KCND3	Likely benign	criteria provided, multiple submitters, no conflicts
698131	NM_001378969.1(KCND3):c.1041G>A (p.Ser347=)	KCND3	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · 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
KCND3	Limited	Autosomal dominant	Brugada syndrome 9	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCND3	Orphanet:130	Brugada syndrome
KCND3	Orphanet:98772	Spinocerebellar ataxia type 19/22
LAMA4	Orphanet:154	Familial isolated dilated cardiomyopathy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KCND3	HGNC:6239	ENSG00000171385	Q9UK17	A-type voltage-gated potassium channel KCND3	gencc,clinvar
LAMA4	HGNC:6484	ENSG00000112769	Q16363	Laminin subunit alpha-4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCND3	A-type voltage-gated potassium channel KCND3	Pore-forming (alpha) subunit of voltage-gated A-type potassium channels that mediates transmembrane potassium transport in excitable membranes, in brain and heart.
LAMA4	Laminin subunit alpha-4	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	55.8×	0.036
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCND3	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv
LAMA4	Other/Unknown	no		EGF, Laminin_G, LE_dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar vermis	1
lateral nuclear group of thalamus	1
substantia nigra pars reticulata	1
lower esophagus	1
lower esophagus muscularis layer	1
nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCND3	262	broad	marker	cerebellar vermis, substantia nigra pars reticulata, lateral nuclear group of thalamus
LAMA4	268	ubiquitous	marker	lower esophagus muscularis layer, lower esophagus, nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LAMA4	2,688
KCND3	2,215

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCND3	Q9UK17	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LAMA4	Q16363	73.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Phase 1 - inactivation of fast Na+ channels	1	815.7×	0.017	KCND3
MET promotes cell motility	1	300.5×	0.017	LAMA4
Attachment of bacteria to epithelial cells	1	248.3×	0.017	LAMA4
Laminin interactions	1	190.3×	0.017	LAMA4
MET activates PTK2 signaling	1	190.3×	0.017	LAMA4
Signaling by MET	1	158.6×	0.017	LAMA4
Formation of the dystrophin-glycoprotein complex (DGC)	1	154.3×	0.017	LAMA4
Voltage gated Potassium channels	1	121.5×	0.017	KCND3
Developmental Lineage of Pancreatic Ductal Cells	1	114.2×	0.017	LAMA4
Non-integrin membrane-ECM interactions	1	77.2×	0.022	LAMA4
ECM proteoglycans	1	75.1×	0.022	LAMA4
Potassium Channels	1	67.2×	0.022	KCND3
Cardiac conduction	1	54.4×	0.025	KCND3
Muscle contraction	1	38.6×	0.033	KCND3
Extracellular matrix organization	1	31.6×	0.038	LAMA4
Signaling by Receptor Tyrosine Kinases	1	25.8×	0.043	LAMA4
Neuronal System	1	22.1×	0.047	KCND3
Signal Transduction	1	5.1×	0.187	LAMA4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 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	2808.7×	0.007	KCND3
membrane repolarization during cardiac muscle cell action potential	1	842.6×	0.007	KCND3
membrane repolarization during ventricular cardiac muscle cell action potential	1	842.6×	0.007	KCND3
membrane repolarization	1	648.1×	0.007	KCND3
potassium ion export across plasma membrane	1	526.6×	0.007	KCND3
protein tetramerization	1	312.1×	0.010	KCND3
regulation of heart contraction	1	247.8×	0.010	KCND3
regulation of heart rate by cardiac conduction	1	187.2×	0.010	KCND3
action potential	1	179.3×	0.010	KCND3
negative regulation of cold-induced thermogenesis	1	172.0×	0.010	LAMA4
regulation of embryonic development	1	165.2×	0.010	LAMA4
regulation of cell adhesion	1	153.2×	0.010	LAMA4
muscle contraction	1	104.0×	0.014	KCND3
potassium ion transport	1	95.8×	0.014	KCND3
regulation of cell migration	1	78.8×	0.016	LAMA4
potassium ion transmembrane transport	1	68.0×	0.017	KCND3
protein homooligomerization	1	61.1×	0.018	KCND3
chemical synaptic transmission	1	38.6×	0.027	KCND3
cell adhesion	1	18.7×	0.053	LAMA4

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
KCND3	DULOXETINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCND3	10	4
LAMA4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DULOXETINE	4	KCND3
DARUNAVIR	4	KCND3
DARIFENACIN	4	KCND3
TOLTERODINE	4	KCND3
VARDENAFIL	4	KCND3
PALIPERIDONE	4	KCND3
SOLIFENACIN	4	KCND3
NEBIVOLOL	4	KCND3
SUNITINIB	4	KCND3
DEFERASIROX	4	KCND3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCND3	118	Binding:55, Functional:44, ADMET:12, Toxicity:7

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
KCND3	118

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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)
DULOXETINE	4	KCND3
DARUNAVIR	4	KCND3
DARIFENACIN	4	KCND3
TOLTERODINE	4	KCND3
VARDENAFIL	4	KCND3
PALIPERIDONE	4	KCND3
SOLIFENACIN	4	KCND3
NEBIVOLOL	4	KCND3
SUNITINIB	4	KCND3
DEFERASIROX	4	KCND3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KCND3
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	LAMA4

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)
LAMA4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.