PharmGKB: The Pharmacogenomics Knowledge Base

Gene:
SCN5A
sodium channel, voltage-gated, type V, alpha subunit

Overview

Alternate Names: Sodium channel, voltage-gated, type V, alpha polypeptide; cardiac sodium channel alpha subunit; cardiomyopathy, dilated 1E (autosomal dominant); sodium channel, voltage-gated, type V, alpha (long QT syndrome 3); sodium channel, voltage-gated, type V, alpha polypeptide (long (electrocardiographic) QT syndrome 3); voltage-gated sodium channel type V alpha
Alternate Symbols: CDCD2; CMD1E; CMPD2; HB1; HB2; HBBD; HH1; ICCD; IVF; LQT3; Nav1.5; PFHB1; SSS1
PharmGKB Accession Id: PA304

Details

Cytogenetic Location: chr3 : p22.2
GP mRNA Boundary†: chr3 : 38564557 - 38666167
GP Gene Boundary†: chr3 : 38561557 - 38676167
Strand: minus
Product Name: cardiac sodium channel alpha subunit, cardiomyopathy, dilated 1E (autosomal dominant), sodium channel, voltage-gated, type V, alpha polypeptide (long (electrocardiographic) QT syndrome 3), voltage-gated sodium channel type V alpha, voltage-gated sodium channel type V alpha isoform a, voltage-gated sodium channel type V alpha isoform b
† The mRNA boundaries are calculated using the gene's default feature set from NCBI, mapped onto the UCSC Golden Path. PharmGKB sets gene boundaries by expanding the mRNA boundaries by no less than 10,000 bases upstream (5') and 3,000 bases downstream (3') to allow for potential regulatory regions.

Introduction

View Full VIP Annotation

The voltage-gated sodium channel type V alpha isoform (NaV1.5) belongs to a superfamily of nine sodium channels that are gated (opened and closed) by changes in membrane potential. The encoded protein is found primarily in cardiac muscle, generates the initial fast upstroke of the action potential in most cardiac cells, and underlies fast conduction in atria and ventricles; sodium channel block prolongs QRS duration on the electrocardiogram. Unlike neuronal sodium channels, the cardiac isoform is relatively resistant to block by the pufferfish toxin tetrodotoxin. The human gene, SCN5A, was cloned by Gellens et al. [PMID: 1309946] in 1992 and localized to chromosome 3p21 by George et al. in 1995 [PMID: 7956363].

The gene consists of 28 exons (generating an mRNA of 8526 nucleotides) with an open reading frame that encodes a 2016-amino acid protein. The coding region of the gene includes four common non-synonymous polymorphisms: R34C, H558R, S1103Y, and R1193Q. One common splice variant: Q1077del [Makielski et al. PMID: 14500339] has been reported.

More than 100 mutations in SCN5A have been associated with a range of congenital human arrhythmia syndromes. Loss of normal fast inactivation results in increased maintained inward plateau current, generating the long QT syndrome type 3 (LQT3) [MIM#603830]. Loss of function variants - through a variety of mechanisms - produce the Brugada syndrome [MIM#601144]. Other arrhythmias reported with SCN5A mutations include autosomal recessive sick sinus syndrome 1 (sss1) [MIM#608567], idiopathic ventricular fibrillation (IVF) [MIM#603829], sudden infant death syndrome (SIDS) [MIM#272120] and progressive familial heart block type I [MIM#113900]. The spectrum of these disease related mutations have been reported in several large scale screening studies [PMID: 15851227, 10973849].

Drugs that block sodium channels include those used for the treatment of arrhythmias as well as a small number of non-antiarrhythmics. Sodium channel blocking antiarrhythmics include quinidine, procainamide, disopyramide, flecainide, propafenone, lidocaine, mexiletine, and amiodarone. Many of these exert other important electrophysiologic, autonomic and other effects. Sodium channel blocking antiarrhythmics have been shown to increase mortality (likely due to ventricular fibrillation) in patients convalescing from myocardial infarction [PMID: 1720917, 2473403, 1377359, 6209318, 6369290]. Drugs not used as antiarrhythmics but that block sodium channels include tricyclic antidepressants, cocaine, and lithium. Administration of sodium channel blocking drugs may unmask the typical electrocardiogram of previously subclinical Brugada syndrome [PMID: 16144991]. In addition, subclinical LQT3 has been reported to be unmasked by administration of the QT-prolonging drug cisapride [PMID:12208804].

In-Depth Annotations (In-Depth Annotation)

  1. rs7626962 at chr3:38595911 in SCN5A
    Has been studied in association with long QT.
    Variant Name:
    SCN5A:S1103Y
    Related Diseases:
    Long QT Syndrome
    Evidence:
    http://www.pharmgkb.org/.../variant.jsp
  2. rs1805124 at chr3:38620424 in SCN5A
    Has been studied in association with long QT.
    Variant Name:
    SCN5A:H558R
    Related Diseases:
    Long QT Syndrome
    Evidence:
    http://www.pharmgkb.org/.../variant.jsp
  3. rs6791924 at chr3:38649703 in SCN5A
    Has been studied in association with long QT.
    Variant Name:
    SCN5A:R34C
    Related Diseases:
    Long QT Syndrome
    Evidence:
    http://www.pharmgkb.org/.../variant.jsp

Non-Curated Annotations (Non-Curated Annotation)

  1. rs11129795 at chr3:38564167 in SCN5A
    GWAS results: Common variants at ten loci modulate the QT interval duration in the QTSCD Study. (Initial Sample Size: 15,842 individuals; Replication Sample Size: up to 13,602 individuals); (Region: 3p22.2; Reported Gene(s): SCN5A; Risk Allele: rs11129795-A); (p-value= 0.00000000000005).This variant is associated with QT interval.
    Evidence:
    PMID:19305409
    http://www.genome.gov/gwastudies/
  2. rs12053903 at chr3:38568397 in SCN5A
    GWAS results: Common variants at ten loci influence QT interval duation in the QTGEN Study. (Initial Sample Size: 13,685 individuals; Replication Sample Size: 15,854 individuals); (Region: 3p22.2; Reported Gene(s): SCN5A; Risk Allele: rs12053903-C); (p-value= 0.00000000000001).This variant is associated with QT interval.
    Evidence:
    PMID:19305408
    http://www.genome.gov/gwastudies/
Variant names are different names that have been used in the literature and other resources to refer to the same variant. Non-curated variant information is accumulated solely by computational methods and has not been verified by the scientific staff at PharmGKB.

Non-Curated Information

A list of non-curated publications that mention this gene along with other genes is available.

PharmGKB Curated Pathways

Curated Information

The following drugs are in curated knowledge about this gene.

  Drug Class Relationship Evidence
No phenotype data No genotype data Literature annotations available Not annotated
antiarrhythmics, class i and iii
  • CO
  • PD
  •   
  • FA
  • GN
Publications, Pathways
No phenotype data No genotype data Literature annotations available Not annotated
Beta blocking agents, selective
  • CO
  •   
  •   
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
qt-prolonging drugs
  •   
  • PD
  •   
  •   
  •   
Publications
  Drug Relationship Evidence
Phenotype data available Genotype Data Available Literature annotations available Not annotated
amiodarone
  •   
  • PD
  •   
  •   
  •   
Publications, Pathways
Phenotype data available Genotype Data Available Literature annotations available Not annotated
arsenic trioxide
  •   
  • PD
  •   
  •   
  •   
Pathways
Phenotype data available Genotype Data Available Literature annotations available Not annotated
cisapride
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
clarithromycin
  •   
  • PD
  •   
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
disopyramide
  •   
  • PD
  •   
  •   
  •   
Pathways
Phenotype data available Genotype Data Available Literature annotations available Not annotated
dofetilide
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
doxorubicin
  •   
  • PD
  •   
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
droperidol
  •   
  • PD
  •   
  •   
  •   
Pathways
Phenotype data available Genotype Data Available Literature annotations available Not annotated
erythromycin
  •   
  • PD
  •   
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
flecainide
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
halofantrine
  •   
  • PD
  •   
  •   
  •   
Pathways
Phenotype data available Genotype Data Available Literature annotations available Not annotated
haloperidol
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
ibutilide
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
lidocaine
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
mesoridazine
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
methadone
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
mexiletine
  •   
  • PD
  •   
  •   
  •   
Publications, Pathways
No phenotype data No genotype data Literature annotations available Not annotated
pentamidine
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
pimozide
  •   
  • PD
  •   
  •   
  •   
Pathways
Phenotype data available Genotype Data Available Literature annotations available Not annotated
procainamide
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
propafenone
  •   
  • PD
  •   
  •   
  •   
Pathways
Phenotype data available Genotype Data Available Literature annotations available Not annotated
quinidine
  •   
  • PD
  •   
  •   
  •   
Pathways
Phenotype data available Genotype Data Available Literature annotations available Not annotated
sotalol
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data Literature annotations available Not annotated
sparfloxacin
  •   
  • PD
  •   
  •   
  •   
Pathways
Phenotype data available Genotype Data Available Literature annotations available Not annotated
sulfamethoxazole
  •   
  • PD
  •   
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
terfenadine
  •   
  • PD
  •   
  •   
  •   
Publications
Phenotype data available No genotype data Literature annotations available Not annotated
thioridazine
  •   
  • PD
  •   
  •   
  •   
Pathways
No phenotype data No genotype data No literature annotations Not annotated
tocainide
  •   
  • PD
  •   
  •   
  •   
Pathways
Phenotype data available Genotype Data Available Literature annotations available Not annotated
trimethoprim
  •   
  • PD
  •   
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
warfarin
  • CO
  •   
  •   
  •   
  • GN
Publications

Non-Curated Information

A list of non-curated publications that mention this gene along with other drugs is available.

Curated Information

The following diseases are in curated knowledge about this gene.

  Disease Relationship Evidence
No phenotype data No genotype data Literature annotations available Not annotated
Abnormalities, Drug-Induced
  •   
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Abortion, Habitual
  • CO
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Alzheimer Disease
  • CO
  •   
  •   
  • FA
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Arrhythmias, Cardiac
  • CO
  •   
  •   
  • FA
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Atrial Fibrillation
  • CO
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Brugada syndrome
  • CO
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Cardiomyopathy, Dilated
  • CO
  •   
  •   
  • FA
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Cardiomyopathy, Hypertrophic
  • CO
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Coronary Artery Disease
  • CO
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Coronary Disease
  • CO
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Death, Sudden, Cardiac
  • CO
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Heart Arrest
  •   
  • PD
  •   
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Heart Diseases
  • CO
  •   
  •   
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Long QT Syndrome
  • CO
  • PD
  •   
  • FA
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Myocardial Infarction
  • CO
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Seizures
  •   
  • PD
  •   
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Sudden Infant Death
  • CO
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Syncope
  •   
  • PD
  •   
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Tachycardia, Ventricular
  •   
  • PD
  •   
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Thromboembolism
  • CO
  •   
  •   
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Torsades de Pointes
  • CO
  • PD
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Ventricular Fibrillation
  • CO
  • PD
  •   
  •   
  • GN
Publications

Non-Curated Information

A list of non-curated publications that mention this gene along with other diseases is available.

Curated Phenotype Datasets

These datasets are sorted alphabetically by title.

  1. Characteristics of Variant Sodium Channels
    • Genotype data available
    • Phenotype data available
    • No literature annotations
    • Not annotated
    • FA
    Submitted by Dan Roden, MD involving SCN5A, qt-prolonging drugs, and Torsades de Pointes
  2. Drug-Induced Long QT Intervals
    • Genotype data available
    • Phenotype data available
    • No literature annotations
    • Not annotated
    • PD
    Submitted by Dan Roden, MD involving ADRB1, ADRB2, KCNE1, KCNE2, KCNH2, KCNQ1, SCN5A, almokalant, amiodarone, amitriptyline, bretylium, bupivacaine, cisapride, disopyramide, dofetilide, encainide, fluconazole, haloperidol, hydroquinidine, isoflurane, itraconazole, ketoconazole, lithium, loratadine, metoclopramide, nortriptyline, procainamide, quinidine, sematilide, sotalol, sulfamethoxazole, thioridazine, trimethoprim, , Long QT Syndrome, Proarrhythmia and Torsades de Pointes

Additional Datasets

These datasets are minimally curated and are sorted alphabetically by title.

  1. A chemogenomic approach to drug discovery: focus on cardiovascular diseases
  2. A Genotype Dependent Intermediate ECG Phenotype in Patients with Persistent Lone Atrial Fibrillation
  3. Cardiac Sodium Channel (SCN5A) Variants Associated with Atrial Fibrillation
  4. Genetic Associations in Drug-induced QT Prolongation and Torsades
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