GeneBe

SCN1B

protein-coding

sodium voltage-gated channel beta subunit 1, the group of Sodium voltage-gated channel beta subunits|V-set domain containing

Gene summary

Voltage-gated sodium channels are heteromeric proteins that function in the generation and propagation of action potentials in muscle and neuronal cells. They are composed of one alpha and two beta subunits, where the alpha subunit provides channel activity and the beta-1 subunit modulates the kinetics of channel inactivation. This gene encodes a sodium channel beta-1 subunit. Mutations in this gene result in generalized epilepsy with febrile seizures plus, Brugada syndrome 5, and defects in cardiac conduction. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

MANE transcript

NM_001037.5

Inheritance

AD, AR

ClinVar variants

P:48U:235B:102

Top phenotype

Atrial fibrillation, familial 13; Brugada syndrome 5

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr19:35,030,470-35,040,449

External References & Databases

Ensembl (ENSG00000105711)NCBI Gene (6324)OMIM (600235)HGNC:10586GenCCUniProt (Q07699)AlphaFoldClinVar (SCN1B)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~10.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Brugada syndrome 5LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013015

Submitter: Labcorp Genetics (formerly Invitae)

atrial fibrillation, familial, 13LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014155

Submitter: Labcorp Genetics (formerly Invitae)

Brugada syndrome 5LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013015

Submitter: Genomics England PanelApp

generalized epilepsy with febrile seizures plus, type 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011416

Submitter: G2P

developmental and epileptic encephalopathy, 52DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0033361

Submitter: G2P

Dravet syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011794

Submitter: Orphanet

progressive familial heart blockSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019490

Submitter: Orphanet

genetic developmental and epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: Orphanet

genetic developmental and epileptic encephalopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100062

Submitter: ClinGen

SCN1B was first reported in relation to autosomal recessive Developmental and Epileptic Encephalopathy in 2009 (Patino, et al., PMID: 19710327). At least 8 variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 probands in 5 publications (PMID: 19710327, 23148524, 28218389, 31709768, 33901312). Variants in this gene segregated with disease in 5 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is biallelic loss of function (PMID: 19710327, 28218389). Of note, this gene has also been implicated in autosomal dominant Generalized Epilepsy with Febrile Seizures plus and autosomal dominant atrial fibrillation or Brugada syndrome. These have been assessed separately. This gene-disease association is supported by animal models, expression studies, and in vitro functional assays. In summary, SCN1B is definitively associated with autosomal recessive Developmental and Epileptic Encephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy Working Group on 1/4/22 (SOP Version 8).

generalized epilepsy with febrile seizures plus, type 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011416

Submitter: Labcorp Genetics (formerly Invitae)

generalized epilepsy with febrile seizures plusDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018214

Submitter: ClinGen

*SCN1B* was first reported in relation to autosomal dominant generalized epilepsy with febrile seizures plus (GEFS+) in 1998 (Wallace et al., PMID: 9697698). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore the following disease entities have been split into multiple disease entities: autosomal dominant GEFS+, autosomal recessive developmental and epileptic encephalopathy (DEE), and autosomal dominant atrial fibrillation or Brugada syndrome. Autosomal recessive DEE has been curated separately by the Epilepsy Gene Curation Expert Panel. This curation focuses only on autosomal dominant GEFS+ and does not include cases with isolated autosomal dominant atrial fibrillation/Brugada syndrome. Eleven variants, including missense, nonsense, and start loss variants, in 15 probands from 11 publications have been included in this curation (PMIDs: 9697698, 14504340, 17020904, 28726809, 30660056, 31729702, 31980526, 35704740, 35886038, 19522081, 12011299). A well-described founder variant (p.Cys121Trp) has also been reported (PMIDs: 9697698, 17020904, 20628201). Variants in this gene were shown to segregate with disease in many additional family members. However, incomplete penetrance (calculated as ~60% in PMID: 9697698) and clinical heterogeneity have been reported. Therefore, there is some uncertainty around whether heterozygous variants in SCN1B might better be described as risk factors as opposed to a typical Mendelian disease of reasonable penetrance. The exact mechanism of disease is currently unknown. This gene-disease relationship is also supported by animal models and biochemical experiments revealing gene function (PMIDs: 20628201, 23090990). In summary, there is definitive evidence supporting the relationship between *SCN1B* and GEFS+. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Of note, this gene-disease pair was originally evaluated by the ClinGen Epilepsy Gene Curation Expert Panel on January 4, 2022. It was reevaluated on December 13, 2022. As a result of this reevaluation, the classification changed from Moderate to Definitive with the addition of new case data (PMIDs: 35704740, 35886038, 19522081, 12011299) and a new mouse model (PMID: 20628201) (SOP Version 9).

generalized epilepsy with febrile seizures plus, type 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011416

Submitter: Illumina

Brugada syndrome 1NO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0011001

Submitter: ClinGen

Brugada syndrome 5MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013015

Submitter: Genomics England PanelApp

generalized epilepsy with febrile seizures plusSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018214

Submitter: Orphanet

developmental and epileptic encephalopathy, 52STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033361

Submitter: Labcorp Genetics (formerly Invitae)

Brugada syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: G2P

Clinical Genomic Database (CGD)

Atrial fibrillation, familial 13; Brugada syndrome 5AD

Manifestation: Cardiovascular; Neurologic

Intervention: Cardiovascular; Pharmacogenomic

Rationale: In Atrial fibrillation, surveillance (eg, with echocardiogram and electrocardiogram) may allow early medical and/or surgical management (eg, atrioventricular nodal ablation followed by dual-chamber pacemaker implantation has been described), which may be beneficial; 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: 9697698; 12011299; 14504340; 18464934; 19808477; 20301690; 23148524; 28218389Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SCN1B variants in ClinVar

25 Conditions Cataloged
Brugada syndrome 5Total: 525
not providedTotal: 223
Cardiovascular phenotypeTotal: 188
not specifiedTotal: 89
Generalized epilepsy with febrile seizures plus, type 1Total: 55
Developmental and epileptic encephalopathy, 52Total: 43
Atrial fibrillation, familial, 13Total: 31
SCN1B-related disorderTotal: 26

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001037.5. 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.

EffectPLPVUSLBBSum
synonymous
9
clinvar
91
clinvar
 100
missense
4
clinvar
10
clinvar
210
clinvar
11
clinvar
 235
nonsense
6
clinvar
3
clinvar
3
clinvar
 12
start loss
1
clinvar
2
clinvar
1
clinvar
 4
frameshift
9
clinvar
2
clinvar
7
clinvar
 18
splice donor/acceptor (+/-2bp)
6
clinvar
5
clinvar
5
clinvar
 16
Total26222351020385

Highest pathogenic variant AF is 0.00010470387

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001037.5RefSeqNP_001028.15MANE Select
ENST00000262631.11EnsemblENSP00000262631.35MANE Select
NM_001321605.2RefSeqNP_001308534.14Standard
NM_199037.5RefSeqNP_950238.13Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
scn1bbDanio rerio

Structure: motor neuron

Quality: branchiness

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Adrenergic signaling in cardiomyocytes - Homo sapiens (human)
  • Antiarrhythmic Pathway, Pharmacodynamics
  • Levomethadyl Acetate Action Action Pathway
  • Fluoxetine Action Pathway
  • Citalopram Action Pathway

Biological Process

  • cell adhesion
  • chemical synaptic transmission
  • axon guidance
  • positive regulation of sodium ion transport
  • positive regulation of neuron projection development

Molecular Function

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

Cellular Component

  • voltage-gated sodium channel complex
  • extracellular region
  • plasma membrane
  • intercalated disc
  • T-tubule

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000415950
Coding exons
3
Length
9765
Individuals with no LoFs
125743
Homozygous LoFs
0
Heterozygous LoFs
3
Defined
125746
p
0.0000119
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.221181620.7290.00001111728
Missense (PolyPhen)2641.1310.63213402
Synonymous-0.06276867.31.010.00000493555
Loss of Function1.2224.910.4072.15e-766

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.00000880.0000088rare
South Asian0.0000330.000033rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Crucial in the assembly, expression, and functional modulation of the heterotrimeric complex of the sodium channel. The subunit beta-1 can modulate multiple alpha subunit isoforms from brain, skeletal muscle, and heart. 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. {ECO:0000269|PubMed:14622265}.;
Disease
DISEASE: Brugada syndrome 5 (BRGDA5) [MIM:612838]: A tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. {ECO:0000269|PubMed:18464934}. Note=The gene represented in this entry may be involved in disease pathogenesis.; DISEASE: Atrial fibrillation, familial, 13 (ATFB13) [MIM:615377]: 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:19808477}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epileptic encephalopathy, early infantile, 52 (EIEE52) [MIM:617350]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE52 inheritance is autosomal recessive. {ECO:0000269|PubMed:19710327, ECO:0000269|PubMed:23148524}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.158

Intolerance Scores

LoFtool
0.0653
RVIS EVS
0.62
RVIS percentile EVS
83.25

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.683

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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