SCN3B

protein-coding

sodium voltage-gated channel beta subunit 3, the group of V-set domain containing|Sodium voltage-gated channel beta subunits

Gene summary

Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel beta subunit gene family, and influences the inactivation kinetics of the sodium channel. Two alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001040151.2

Inheritance

ClinVar variants

P:2U:117B:74

Top phenotype

Brugada syndrome 7; Atrial fibrillation, familial 16

gnomAD constraint

pLI —, LoF o/e 0.35

Max pathogenic AF

—

Genomic locus

chr11:123,629,187-123,655,244

External References & Databases

Ensembl (ENSG00000166257)

Transcript & Mutation Effects

hg38 • Region Span ~26.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Brugada syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: ClinGen

SCN3B encodes the sodium channel β-subunit 3 (known as Navβ3). SCN3B was first reported in relation to autosomal dominant Brugada syndrome in 2009 (Hu et al., PMID: 20031595). Navβ3 variants have been suggested to cause cardiac disease by modulating the trafficking of Nav1.5 to the cell membrane or by affecting the function of the Nav1.5 channel (PMID: 20031595, 23257389, 38450374, 20042427, 39761910). Homozygous knockout mouse models implicate SCN3B in cardiac disease, with reports of electrophysiological abnormalities including shorter ventricular effective refractory periods and increased susceptibility to ventricular tachycardia following programmed electrical stimulation (PMID: 19351516). Evidence of perturbed atrial function with increased susceptibility to atrial tachycardia and fibrillation following atrial burst pacing has also been reported (PMID: 19796257). Immunoprecipitation experiments also show that Navβ3 interacts with Nav1.5 (PMID: 20042427, 39761910). However, there is significant evidence suggesting that SCN3B variants are not a monogenic cause of autosomal dominant Brugada syndrome. This contradictory evidence includes evidence that some of the reported variants have high allele frequencies (PMID: 20031595, 23257389) and the fact that SCN3B also has very low mRNA expression in the heart (left ventricle TPM = ~0.5, GTEx), with SCN5A exhibiting much higher expression (left ventricle TPM = ~36, GTEx). Further, most of the functional work performed to assess SCN3B variants as having an impact on sodium current has been performed by co-expressing Navβ3 variants with Nav1.5 in cell models (PMIDs: 20031595, 23257389, 26179811, 39761910, 38450374, 21051419, 34867379). Given that SCN3B has low mRNA abundance within cardiac tissue, these models may overestimate the physiological effects of SCN3B variants on Nav1.5 function. SCN3B homozygous loss-of-function has also been reported in two consanguineous families with a neurodevelopmental disorder with no cardiovascular phenotype being reported in either heterozygous or homozygous carriers of truncating variants (PMID: 40879121). While homozygous knockout mouse models report evidence of perturbed electrophysiological function (PMIDs: 19351516, 19796257), these animal studies model a more severe genetic defect than the heterozygous missense variants reported in the literature. Finally, burden testing has failed to identify any statistically significant enrichment of SCN3B variants in patients with Brugada syndrome relative to controls (PMIDs: 25650408, 26220970). The relationship between SCN3B and autosomal dominant Brugada syndrome was originally evaluated by the ClinGen Brugada Syndrome Gene Curation Expert Panel in 2017 and was classified as disputed. This gene-disease pair was re-evaluated by the Hereditary Cardiovascular Disorders GCEP on 25 November, 2025. Following re-evaluation and the consideration of new evidence, the gene-disease classification was changed to refuted. This classification was approved by the ClinGen Hereditary Cardiovascular Disorders GCEP on 25 November, 2025 (in accordance with SOP Version 11).

Brugada syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: G2P

Brugada syndrome 7LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013146

Submitter: Genomics England PanelApp

atrial fibrillationNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0004981

Submitter: ClinGen

SCN3B encodes the sodium channel β-subunit 3 (Navβ3). SCN3B variants were first reported in atrial fibrillation cohorts in 2010 (Wang et al. PMID: 20558140; Olesen et al. PMID: 21051419). Navβ3 variants have been suggested to cause cardiac disease by modulating the trafficking of Nav1.5 to the cell membrane or by affecting the function of the Nav1.5 channel (PMID: 20031595, 23257389, 38450374, 20042427, 39761910). Homozygous knockout mouse models implicate SCN3B in cardiac disease, with reports of electrophysiological abnormalities including shorter ventricular effective refractory periods and increased susceptibility to ventricular tachycardia following programmed electrical stimulation (PMID: 19351516). Evidence of perturbed atrial function with increased susceptibility to atrial tachycardia and fibrillation following atrial burst pacing has been reported (PMID: 19796257). Immunoprecipitation experiments also show that Navβ3 interacts with Nav1.5 (PMID: 20042427, 39761910). There are a handful of publications reporting SCN3B variants in cases of atrial fibrillation (PMIDs: 20558140, PMID: 21051419, PMID: 36362949). However, there is also significant evidence suggesting that SCN3B variants are not a monogenic cause of autosomal dominant atrial fibrillation. Notably, SCN3B has very low mRNA expression in the heart (left ventricle TPM = ~0.5, GTEx), with SCN5A exhibiting much higher expression (left ventricle TPM = ~36, GTEx). Further, most of the functional work performed to assess SCN3B variants as having an impact on sodium current has been performed by co-expressing Navβ3 variants with Nav1.5 in cell models (PMIDs: 20031595, 23257389, 26179811, 39761910, 38450374, 21051419, 34867379). Since SCN3B has low mRNA abundance in cardiac tissue, these models may overestimate the effects of SCN3B variants on Nav1.5 function in vivo. SCN3B homozygous loss-of-function has also been reported in two consanguineous families with a neurodevelopmental disorder with no cardiovascular phenotype being reported in either heterozygous or homozygous carriers of truncating variants (PMID: 40879121). While homozygous knockout mouse models report evidence of perturbed electrophysiological function (PMIDs: 19351516, 19796257), these animal studies model a more severe genetic defect than the heterozygous missense variants reported in the literature. This gene-disease relationship was evaluated on 25 November 2025, by the Hereditary Cardiovascular Disorders GCEP. For the reasons highlighted above, this gene-disease classification is disputed. This classification was approved by the ClinGen HCVD GCEP on 25 November 2025 (in accordance with SOP Version 11).

Brugada syndrome 7LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0013146

Submitter: Labcorp Genetics (formerly Invitae)

Brugada syndrome 7LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013146

Submitter: Labcorp Genetics (formerly Invitae)

familial atrial fibrillationSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018054

Submitter: Orphanet

Clinical Genomic Database (CGD)

Brugada syndrome 7; Atrial fibrillation, familial 16AD

Manifestation: Cardiovascular

Intervention: Cardiovascular; Pharmacogenomic

Rationale: In Atrial fibrilliation, medical/preventive management may decrease morbidity; In Brugada syndrome, surveillance with approximately yearly EKG and medical interventions, including daily quinidine for prevention (though treatment of asymptomatic individuals is controversial), ICD placement in individuals with previous cardiac arrest/syncope, and isoproterenol for electrical storms, may be beneficial; Certain agents should be avoided, including medications such as certain anesthetics, antidepressants, and antipsychotics, and care should be taken in the instance of high fever

Refs: 20031595; 20301690; 20558140; 21051419

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SCN3B variants in ClinVar

11 Conditions Cataloged

Cardiovascular phenotypeTotal: 141

Brugada syndrome 7Total: 125

not providedTotal: 46

not specifiedTotal: 34

Atrial fibrillation, familial, 16Total: 4

SCN3B-related disorderTotal: 4

Brugada syndromeTotal: 2

Cardiac arrhythmiaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001040151.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	60 clinvar	2 clinvar	63
missense	2 clinvar		102 clinvar	12 clinvar		116
nonsense			4 clinvar			4
start loss						0
frameshift			4 clinvar			4
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	2	0	117	72	2	193

Highest pathogenic variant AF is 0.000001368165

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001040151.2	RefSeq	NP_001035241.1	5	MANE Select
ENST00000299333.8	Ensembl	ENSP00000299333.3	5	MANE Select
NM_018400.4	RefSeq	NP_060870.1	5	Standard
ENST00000392770.6	Ensembl	ENSP00000376523.2	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Antiarrhythmic Pathway, Pharmacodynamics
Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways
Developmental Biology
Phase 0 - rapid depolarisation
Cardiac conduction

Biological Process

sodium ion transport
nervous system development
positive regulation of heart rate
positive regulation of sodium ion transport
sensory perception of pain

Molecular Function

voltage-gated ion channel activity
voltage-gated sodium channel activity
sodium channel regulator activity
sodium channel inhibitor activity
ion channel binding

Cellular Component

voltage-gated sodium channel complex
plasma membrane
integral component of membrane
Z disc

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000392770
Coding exons: 5
Length: 26058
Individuals with no LoFs: 125742
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125747
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.794	100	125	0.800	0.00000822	1400
Missense (PolyPhen)		33	43.125	0.76522		480
Synonymous	0.0743	52	52.7	0.987	0.00000376	418
Loss of Function	2.04	4	11.4	0.350	5.97e-7	131

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Modulates channel gating kinetics. Causes unique persistent sodium currents. Inactivates the sodium channel opening more slowly than the subunit beta-1. Its association with NFASC may target the sodium channels to the nodes of Ranvier of developing axons and retain these channels at the nodes in mature myelinated axons (By similarity). {ECO:0000250}.;
Disease: DISEASE: Atrial fibrillation, familial, 16 (ATFB16) [MIM:613120]: A familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. {ECO:0000269|PubMed:20558140, ECO:0000269|PubMed:21051419}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.149

Intolerance Scores

LoFtool: 0.182
RVIS EVS: -0.27
RVIS percentile EVS: 33.97

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.512

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium