Sick sinus syndrome 1

Summary

Sick sinus syndrome 1 (MONDO:0024562) is a disease caused by SCN5A (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SCN5A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 417

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	sick sinus syndrome 1
Mondo ID	MONDO:0024562
OMIM	608567
UMLS	C1837845
MedGen	325270
GARD	0025432
Is cancer (heuristic)	no

Also known as: SCN5A sick sinus syndrome · sick sinus syndrome 1 · sick sinus syndrome caused by mutation in SCN5A · SSS1

Data availability: 417 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart conduction disease › sinoatrial node disorder › sick sinus syndrome › familial sick sinus syndrome › sick sinus syndrome 1

Related subtypes (3): sick sinus syndrome 2, autosomal dominant, sinus node disease and myopia, sick sinus syndrome 4

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

417 retrieved; paginated sample, class counts are floors:

220 uncertain significance, 129 conflicting classifications of pathogenicity, 37 benign/likely benign, 16 pathogenic/likely pathogenic, 6 likely benign, 6 pathogenic, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3376789	NM_000335.5(SCN5A):c.3316G>T (p.Glu1106Ter)	LOC110121269	Pathogenic	criteria provided, single submitter
201438	NM_000335.5(SCN5A):c.664C>T (p.Arg222Ter)	SCN5A	Pathogenic	criteria provided, multiple submitters, no conflicts
201508	NM_000335.5(SCN5A):c.4242+1G>C	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
201560	NM_000335.5(SCN5A):c.2550_2551dup (p.Phe851fs)	SCN5A	Pathogenic	criteria provided, multiple submitters, no conflicts
201572	NM_000335.5(SCN5A):c.4844TCT[1] (p.Phe1616del)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39444	NM_000335.5(SCN5A):c.665G>A (p.Arg222Gln)	SCN5A	Pathogenic	criteria provided, multiple submitters, no conflicts
406415	NM_000335.5(SCN5A):c.5414_5417del (p.Thr1805fs)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523568	NM_000335.5(SCN5A):c.1613del (p.Gly538fs)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, single submitter
67633	NM_000335.5(SCN5A):c.1099C>T (p.Arg367Cys)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67639	NM_000335.5(SCN5A):c.1127G>A (p.Arg376His)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67731	NM_000335.5(SCN5A):c.2440C>T (p.Arg814Trp)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67778	NM_000335.5(SCN5A):c.310C>T (p.Arg104Trp)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67838	NM_000335.5(SCN5A):c.3953G>T (p.Gly1318Val)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67927	NM_000335.5(SCN5A):c.481G>A (p.Glu161Lys)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67932	NM_000335.5(SCN5A):c.4856C>T (p.Thr1619Met)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67967	NM_000335.5(SCN5A):c.5224G>A (p.Gly1742Arg)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68032	NM_000335.5(SCN5A):c.673C>T (p.Arg225Trp)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9374	NM_000335.5(SCN5A):c.4864C>T (p.Arg1622Ter)	SCN5A	Pathogenic	criteria provided, multiple submitters, no conflicts
9377	NM_000335.5(SCN5A):c.5347G>A (p.Glu1783Lys)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9383	NM_000335.5(SCN5A):c.5126C>T (p.Ser1709Leu)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9395	NM_000335.5(SCN5A):c.4219G>A (p.Gly1407Arg)	SCN5A	Pathogenic	criteria provided, multiple submitters, no conflicts
9406	NM_000335.5(SCN5A):c.4780G>C (p.Asp1594His)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3252218	NM_000335.5(SCN5A):c.2425_2426del (p.Ser809fs)	SCN5A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3383167	NM_000335.5(SCN5A):c.3741T>G (p.Tyr1247Ter)	SCN5A	Likely pathogenic	criteria provided, single submitter
4071999	NM_000335.5(SCN5A):c.1122G>C (p.Trp374Cys)	SCN5A	Likely pathogenic	criteria provided, single submitter
178130	NM_000335.5(SCN5A):c.3259G>A (p.Ala1087Thr)	LOC110121269	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178131	NM_000335.5(SCN5A):c.3246C>T (p.Ser1082=)	LOC110121269	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
264627	NM_000335.5(SCN5A):c.3315C>T (p.Ala1105=)	LOC110121269	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
520458	NM_000335.5(SCN5A):c.3080G>A (p.Arg1027Gln)	LOC110121269	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
532068	NM_000335.5(SCN5A):c.3301G>A (p.Ala1101Thr)	LOC110121269	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · Orphanet: 8 · 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
SCN5A	Strong	Autosomal recessive	sick sinus syndrome 1	23

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN5A	Orphanet:101016	Romano-Ward syndrome
SCN5A	Orphanet:130	Brugada syndrome
SCN5A	Orphanet:1344	Isolated atrial standstill
SCN5A	Orphanet:154	Familial isolated dilated cardiomyopathy
SCN5A	Orphanet:166282	Hereditary sick sinus syndrome
SCN5A	Orphanet:228140	Idiopathic ventricular fibrillation
SCN5A	Orphanet:334	Hereditary atrial fibrillation
SCN5A	Orphanet:871	Hereditary progressive cardiac conduction defect

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
SCN5A	HGNC:10593	ENSG00000183873	Q14524	Sodium channel protein type 5 subunit alpha	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN5A	Sodium channel protein type 5 subunit alpha	Pore-forming subunit of Nav1.5, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.

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)
SCN5A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a5su

Expression context

Cohort genes with no expression data: 0.

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
apex of heart	1
cardiac ventricle	1
heart left ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN5A	161	broad	yes	apex of heart, heart left ventricle, cardiac ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCN5A	2,090

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN5A	Q14524	16

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Interaction between L1 and Ankyrins	1	368.4×	0.012	SCN5A
Phase 0 - rapid depolarisation	1	346.1×	0.012	SCN5A
L1CAM interactions	1	120.2×	0.018	SCN5A
Cardiac conduction	1	108.8×	0.018	SCN5A
Muscle contraction	1	77.2×	0.021	SCN5A
Axon guidance	1	45.1×	0.027	SCN5A
Nervous system development	1	42.9×	0.027	SCN5A
Developmental Biology	1	14.5×	0.069	SCN5A

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
bundle of His cell action potential	1	8426.0×	0.001	SCN5A
AV node cell to bundle of His cell communication	1	8426.0×	0.001	SCN5A
membrane depolarization during Purkinje myocyte cell action potential	1	5617.3×	0.001	SCN5A
membrane depolarization during bundle of His cell action potential	1	5617.3×	0.001	SCN5A
membrane depolarization during atrial cardiac muscle cell action potential	1	5617.3×	0.001	SCN5A
AV node cell action potential	1	4213.0×	0.001	SCN5A
membrane depolarization during AV node cell action potential	1	3370.4×	0.001	SCN5A
membrane depolarization during SA node cell action potential	1	3370.4×	0.001	SCN5A
regulation of ventricular cardiac muscle cell membrane depolarization	1	2808.7×	0.001	SCN5A
SA node cell action potential	1	2808.7×	0.001	SCN5A
cardiac ventricle development	1	2407.4×	0.001	SCN5A
response to denervation involved in regulation of muscle adaptation	1	2407.4×	0.001	SCN5A
regulation of atrial cardiac muscle cell membrane repolarization	1	2407.4×	0.001	SCN5A
brainstem development	1	2106.5×	0.001	SCN5A
positive regulation of action potential	1	2106.5×	0.001	SCN5A
regulation of atrial cardiac muscle cell membrane depolarization	1	1872.4×	0.001	SCN5A
membrane depolarization during action potential	1	1685.2×	0.001	SCN5A
atrial cardiac muscle cell action potential	1	1685.2×	0.001	SCN5A
membrane depolarization during cardiac muscle cell action potential	1	1404.3×	0.001	SCN5A
regulation of cardiac muscle cell contraction	1	1123.5×	0.002	SCN5A
cardiac conduction system development	1	1053.2×	0.002	SCN5A
regulation of sodium ion transmembrane transport	1	1053.2×	0.002	SCN5A
telencephalon development	1	991.3×	0.002	SCN5A
ventricular cardiac muscle cell action potential	1	991.3×	0.002	SCN5A
positive regulation of sodium ion transport	1	842.6×	0.002	SCN5A
regulation of ventricular cardiac muscle cell membrane repolarization	1	842.6×	0.002	SCN5A
cardiac muscle cell action potential involved in contraction	1	702.2×	0.002	SCN5A
membrane depolarization	1	510.7×	0.003	SCN5A
regulation of heart rate	1	468.1×	0.003	SCN5A
cardiac muscle contraction	1	401.2×	0.003	SCN5A

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
SCN5A	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN5A	108	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	SCN5A
IMIPRAMINE	4	SCN5A
DROPERIDOL	4	SCN5A
PONATINIB	4	SCN5A
DULOXETINE	4	SCN5A
PALONOSETRON	4	SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	SCN5A
FEDRATINIB	4	SCN5A
QUINIDINE	4	SCN5A
DARUNAVIR	4	SCN5A
DARIFENACIN	4	SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	SCN5A
RANOLAZINE	4	SCN5A
PIMOZIDE	4	SCN5A
NIMODIPINE	4	SCN5A
FELODIPINE	4	SCN5A
NICARDIPINE	4	SCN5A
AMLODIPINE	4	SCN5A
PHENYTOIN	4	SCN5A
PALIPERIDONE	4	SCN5A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SCN5A	594	Binding:380, Functional:98, ADMET:72, Toxicity:43, Unclassified:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN5A	594

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

30 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)
BEPRIDIL	4	SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	SCN5A
IMIPRAMINE	4	SCN5A
DROPERIDOL	4	SCN5A
PONATINIB	4	SCN5A
DULOXETINE	4	SCN5A
PALONOSETRON	4	SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	SCN5A
FEDRATINIB	4	SCN5A
QUINIDINE	4	SCN5A
DARUNAVIR	4	SCN5A
DARIFENACIN	4	SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	SCN5A
RANOLAZINE	4	SCN5A
PIMOZIDE	4	SCN5A
NIMODIPINE	4	SCN5A
FELODIPINE	4	SCN5A
NICARDIPINE	4	SCN5A
AMLODIPINE	4	SCN5A
PHENYTOIN	4	SCN5A
PALIPERIDONE	4	SCN5A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SCN5A
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.