Brugada syndrome 5

Summary

Brugada syndrome 5 (MONDO:0013015) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 558

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Brugada syndrome 5
Mondo ID	MONDO:0013015
OMIM	612838
DOID	DOID:0110222
UMLS	C2748541
MedGen	411607
GARD	0015584
Is cancer (heuristic)	no

Also known as: BRGDA5 · Brugada syndrome 5 · Brugada syndrome caused by mutation in SCN1B · Brugada syndrome type 5 · SCN1B Brugada syndrome

Data availability: 558 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart conduction disease › Brugada syndrome › Brugada syndrome 5

Related subtypes (8): Brugada syndrome 1, Brugada syndrome 2, Brugada syndrome 3, Brugada syndrome 4, Brugada syndrome 6, Brugada syndrome 7, Brugada syndrome 8, Brugada syndrome 9

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

558 retrieved; paginated sample, class counts are floors:

300 uncertain significance, 126 likely benign, 57 conflicting classifications of pathogenicity, 35 benign/likely benign, 19 pathogenic, 14 benign, 5 pathogenic/likely pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1376394	NM_001037.5(SCN1B):c.219T>G (p.Tyr73Ter)	SCN1B	Pathogenic	criteria provided, single submitter
1449534	NM_001037.5(SCN1B):c.304C>T (p.Gln102Ter)	SCN1B	Pathogenic	criteria provided, single submitter
190859	NM_001037.5(SCN1B):c.253C>T (p.Arg85Cys)	SCN1B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190872	NM_001037.5(SCN1B):c.472G>A (p.Val158Met)	SCN1B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
196303	NM_001037.5(SCN1B):c.347del (p.Ser116fs)	SCN1B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2014378	NM_001037.5(SCN1B):c.312_315del (p.Ile106fs)	SCN1B	Pathogenic	criteria provided, single submitter
2031780	NM_001037.5(SCN1B):c.518G>A (p.Trp173Ter)	SCN1B	Pathogenic	criteria provided, single submitter
2035464	NM_001037.5(SCN1B):c.447del (p.Ala150fs)	SCN1B	Pathogenic	criteria provided, single submitter
2123799	NM_001037.5(SCN1B):c.448+10del	SCN1B	Pathogenic	criteria provided, single submitter
2709805	NM_001037.5(SCN1B):c.178dup (p.Arg60fs)	SCN1B	Pathogenic	criteria provided, single submitter
2728379	NM_001037.5(SCN1B):c.59dup (p.Cys21fs)	SCN1B	Pathogenic	criteria provided, single submitter
2728854	NM_001037.5(SCN1B):c.105del (p.Phe36fs)	SCN1B	Pathogenic	criteria provided, single submitter
2762136	NM_001037.5(SCN1B):c.94_95insC (p.Tyr32fs)	SCN1B	Pathogenic	criteria provided, single submitter
2891167	NM_001037.5(SCN1B):c.3G>A (p.Met1Ile)	SCN1B	Pathogenic	criteria provided, single submitter
3644786	NM_001037.5(SCN1B):c.20del (p.Ala6_Leu7insTer)	SCN1B	Pathogenic	criteria provided, single submitter
3672329	NM_001037.5(SCN1B):c.166G>T (p.Glu56Ter)	SCN1B	Pathogenic	criteria provided, single submitter
3726861	NM_001037.5(SCN1B):c.24_25insT (p.Val9fs)	SCN1B	Pathogenic	criteria provided, single submitter
4720677	NM_001037.5(SCN1B):c.77C>A (p.Ser26Ter)	SCN1B	Pathogenic	criteria provided, single submitter
4726829	NM_001037.5(SCN1B):c.357C>A (p.Tyr119Ter)	SCN1B	Pathogenic	criteria provided, single submitter
4728335	NM_001037.5(SCN1B):c.178del (p.Arg60fs)	SCN1B	Pathogenic	criteria provided, single submitter
60767	NM_001037.5(SCN1B):c.254G>A (p.Arg85His)	SCN1B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
694617	NM_001037.5(SCN1B):c.449-2A>G	SCN1B	Pathogenic	reviewed by expert panel
855779	NM_001037.5(SCN1B):c.207+1G>A	SCN1B	Pathogenic	criteria provided, single submitter
9252	NM_001037.5(SCN1B):c.363C>G (p.Cys121Trp)	SCN1B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2146865	NM_001037.5(SCN1B):c.449-1G>T	SCN1B	Likely pathogenic	criteria provided, single submitter
839639	NM_001037.5(SCN1B):c.40+1_40+50del	SCN1B	Likely pathogenic	criteria provided, single submitter
1040220	NM_001037.5(SCN1B):c.3G>C (p.Met1Ile)	SCN1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1062629	NM_001037.5(SCN1B):c.448+114C>G	SCN1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1191122	NM_001037.5(SCN1B):c.2T>C (p.Met1Thr)	SCN1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1274828	NM_001037.5(SCN1B):c.448+346G>A	SCN1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · 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
SCN1B	Moderate	Autosomal dominant	Brugada syndrome 5	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN1B	Orphanet:130	Brugada syndrome
SCN1B	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SCN1B	Orphanet:33069	Dravet syndrome
SCN1B	Orphanet:334	Hereditary atrial fibrillation
SCN1B	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN1B	Orphanet:871	Hereditary progressive cardiac conduction defect
PSENEN	Orphanet:79145	Dowling-Degos disease

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
SCN1B	HGNC:10586	ENSG00000105711	Q07699	Sodium channel regulatory subunit beta-1	gencc,clinvar
PSENEN	HGNC:30100	ENSG00000205155	Q9NZ42	Gamma-secretase subunit PEN-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN1B	Sodium channel regulatory subunit beta-1	Regulatory subunit of multiple voltage-gated sodium (Nav) channels directly mediating the depolarization of excitable membranes.
PSENEN	Gamma-secretase subunit PEN-2	Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein).

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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN1B	Antibody/Immunoglobulin	yes		Ig_V-set, Ig-like_fold, Na_channel_b1/b3
PSENEN	Other/Unknown	no		Gamma_Secretase_Asp_P_PEN2

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
cerebellum	1
primary visual cortex	1
right hemisphere of cerebellum	1
olfactory segment of nasal mucosa	1
right testis	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN1B	133	ubiquitous	marker	primary visual cortex, right hemisphere of cerebellum, cerebellum
PSENEN	140	ubiquitous	marker	right uterine tube, olfactory segment of nasal mucosa, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCN1B	1,328
PSENEN	1,088

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN1B	Q07699	39
PSENEN	Q9NZ42	27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. 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
Noncanonical activation of NOTCH3	1	713.8×	0.012	PSENEN
Regulated proteolysis of p75NTR	1	519.1×	0.012	PSENEN
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	519.1×	0.012	PSENEN
TGFBR3 PTM regulation	1	475.8×	0.012	PSENEN
NRIF signals cell death from the nucleus	1	356.9×	0.012	PSENEN
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	237.9×	0.012	PSENEN
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	219.6×	0.012	PSENEN
Interaction between L1 and Ankyrins	1	184.2×	0.012	SCN1B
Activated NOTCH1 Transmits Signal to the Nucleus	1	178.4×	0.012	PSENEN
Nuclear signaling by ERBB4	1	173.0×	0.012	PSENEN
Phase 0 - rapid depolarisation	1	173.0×	0.012	SCN1B
Sensory perception of taste	1	167.9×	0.012	SCN1B
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	139.3×	0.013	SCN1B
EPH-ephrin mediated repulsion of cells	1	109.8×	0.015	PSENEN
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	98.5×	0.015	PSENEN
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	98.5×	0.015	PSENEN
L1CAM interactions	1	60.1×	0.023	SCN1B
Cardiac conduction	1	54.4×	0.024	SCN1B
Amyloid fiber formation	1	51.4×	0.024	PSENEN
Sensory Perception	1	47.6×	0.025	SCN1B
Muscle contraction	1	38.6×	0.029	SCN1B
Axon guidance	1	22.6×	0.048	SCN1B
Nervous system development	1	21.5×	0.048	SCN1B
Developmental Biology	1	7.2×	0.134	SCN1B

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
corticospinal neuron axon guidance	1	8426.0×	0.003	SCN1B
positive regulation of endopeptidase activity	1	2808.7×	0.003	PSENEN
membrane depolarization during Purkinje myocyte cell action potential	1	2808.7×	0.003	SCN1B
positive regulation of voltage-gated sodium channel activity	1	2808.7×	0.003	SCN1B
Notch receptor processing	1	936.2×	0.003	PSENEN
amyloid-beta formation	1	936.2×	0.003	PSENEN
regulation of atrial cardiac muscle cell membrane depolarization	1	936.2×	0.003	SCN1B
cardiac conduction	1	842.6×	0.003	SCN1B
membrane depolarization during action potential	1	842.6×	0.003	SCN1B
locomotion	1	766.0×	0.003	SCN1B
neuronal action potential propagation	1	702.2×	0.003	SCN1B
membrane depolarization during cardiac muscle cell action potential	1	702.2×	0.003	SCN1B
amyloid precursor protein metabolic process	1	648.1×	0.003	PSENEN
membrane protein intracellular domain proteolysis	1	601.9×	0.003	PSENEN
amyloid precursor protein catabolic process	1	601.9×	0.003	PSENEN
regulation of sodium ion transmembrane transport	1	526.6×	0.003	SCN1B
positive regulation of sodium ion transport	1	421.3×	0.004	SCN1B
regulation of ventricular cardiac muscle cell membrane repolarization	1	421.3×	0.004	SCN1B
cardiac muscle cell action potential involved in contraction	1	351.1×	0.004	SCN1B
membrane protein ectodomain proteolysis	1	324.1×	0.004	PSENEN
membrane depolarization	1	255.3×	0.005	SCN1B
cardiac muscle contraction	1	200.6×	0.007	SCN1B
regulation of heart rate by cardiac conduction	1	187.2×	0.007	SCN1B
sodium ion transmembrane transport	1	101.5×	0.012	SCN1B
protein processing	1	85.1×	0.014	PSENEN
Notch signaling pathway	1	70.8×	0.016	PSENEN
positive regulation of neuron projection development	1	68.5×	0.016	SCN1B
axon guidance	1	45.3×	0.023	SCN1B
cell adhesion	1	18.7×	0.053	SCN1B

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 0

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
PSENEN	NIROGACESTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSENEN	8	4
SCN1B	2	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIROGACESTAT	4	PSENEN
TARENFLURBIL	3	PSENEN
SEMAGACESTAT	3	PSENEN
DS-1971	2	SCN1B
PF-05089771	2	SCN1B
AVAGACESTAT	2	PSENEN
RG-4733	2	PSENEN
BEGACESTAT	2	PSENEN
E-2212	1	PSENEN
MK-0752	1	PSENEN

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PSENEN	487	Binding:464, Functional:16, ADMET:6, Unclassified:1
SCN1B	15	Binding:7, ADMET:6, Toxicity:2

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PSENEN	487

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)
NIROGACESTAT	4	PSENEN
TARENFLURBIL	3	PSENEN
SEMAGACESTAT	3	PSENEN
DS-1971	2	SCN1B
PF-05089771	2	SCN1B
AVAGACESTAT	2	PSENEN
RG-4733	2	PSENEN
BEGACESTAT	2	PSENEN
E-2212	1	PSENEN
MK-0752	1	PSENEN

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PSENEN
B	Phased (≥1) drug, not yet approved	1	SCN1B
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.