Gene:

SCN5A

sodium channel, voltage-gated, type V, alpha subunit

Overview

Details

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 ()

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 ()

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/
   

Non-Curated Information

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

PharmGKB Curated Pathways

• Antiarrhythmic Drug Pathway

Curated Information

The following drugs are in curated knowledge about this gene.

	Drug Class	Relationship	Evidence
	antiarrhythmics, class i and iii	CO PD    FA GN	Publications
	Beta blocking agents, selective	CO          GN	Publications
	qt-prolonging drugs	PD	Publications

	Drug	Relationship	Evidence
	amiodarone	PD	Publications
	clarithromycin	PD	Publications
	doxorubicin	PD	Publications
	erythromycin	PD	Publications
	mexiletine	PD	Publications
	sulfamethoxazole	PD	Publications
	terfenadine	PD	Publications
	trimethoprim	PD	Publications
	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
	Abnormalities, Drug-Induced	GN	Publications
	Abortion, Habitual	CO          GN	Publications
	Alzheimer Disease	CO       FA GN	Publications
	Arrhythmias, Cardiac	CO       FA GN	Publications
	Atrial Fibrillation	CO          GN	Publications
	Brugada syndrome	CO          GN	Publications
	Cardiomyopathy, Dilated	CO       FA GN	Publications
	Cardiomyopathy, Hypertrophic	CO          GN	Publications
	congenital long QT syndrome	CO          GN	Publications
	Coronary Artery Disease	CO          GN	Publications
	Coronary Disease	CO          GN	Publications
	Death, Sudden, Cardiac	CO          GN	Publications
	Heart Arrest	PD	Publications
	Heart Diseases	CO          GN	Publications
	Long QT Syndrome	CO PD    FA GN	Publications, Variants
	Myocardial Infarction	CO          GN	Publications
	Seizures	PD	Publications
	Sudden Infant Death	CO          GN	Publications
	Syncope	PD	Publications
	Tachycardia, Ventricular	PD	Publications
	Thromboembolism	CO          GN	Publications
	Torsades de Pointes	CO PD       GN	Publications
	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

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   • FA

   Submitted by Dan Roden, MD involving SCN5A, qt-prolonging drugs, and Torsades de Pointes
2. Drug-Induced Long QT Intervals

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   • 
   • 
   • 
   • 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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LinkOuts

Common Searches

• Comparative Genomics at UCSC
• Search BioCarta and KEGG Pathways at CGAP
• Search Reactome

Non-Curated Publications

A list of non-curated publications that mention this gene is available.