SCN5A

sodium voltage-gated channel alpha subunit 5, the group of Sodium voltage-gated channel alpha subunits

Basic information

Region (hg38): 3:38548056-38649687

Previous symbols: [ "CMD1E" ]

Links

ENSG00000183873 ∙ NCBI:6331 ∙ OMIM:600163 ∙ HGNC:10593 ∙ Uniprot:Q14524 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Brugada syndrome 1 (Strong), mode of inheritance: AD
• progressive familial heart block, type 1A (Strong), mode of inheritance: AD
• progressive familial heart block, type 1A (Moderate), mode of inheritance: Semidominant
• long QT syndrome 3 (Definitive), mode of inheritance: AD
• Brugada syndrome 1 (Definitive), mode of inheritance: AD
• Brugada syndrome 1 (Definitive), mode of inheritance: AD
• familial isolated dilated cardiomyopathy (Supportive), mode of inheritance: AD
• progressive familial heart block (Supportive), mode of inheritance: AD
• atrial standstill (Supportive), mode of inheritance: AD
• Brugada syndrome (Supportive), mode of inheritance: AD
• familial atrial fibrillation (Supportive), mode of inheritance: AD
• familial sick sinus syndrome (Supportive), mode of inheritance: AD
• paroxysmal familial ventricular fibrillation (Supportive), mode of inheritance: AD
• dilated cardiomyopathy 1E (Definitive), mode of inheritance: AD
• Brugada syndrome 1 (Definitive), mode of inheritance: AD
• long QT syndrome 3 (Definitive), mode of inheritance: AD
• long QT syndrome 3 (Strong), mode of inheritance: AD
• Brugada syndrome 1 (Strong), mode of inheritance: AD
• dilated cardiomyopathy 1E (Strong), mode of inheritance: AD
• sick sinus syndrome 1 (Strong), mode of inheritance: AR
• sick sinus syndrome 1 (Limited), mode of inheritance: AD
• Brugada syndrome (Definitive), mode of inheritance: AD
• arrhythmogenic right ventricular cardiomyopathy (Limited), mode of inheritance: AD
• dilated cardiomyopathy (Definitive), mode of inheritance: AD
• familial long QT syndrome (Definitive), mode of inheritance: AD
• short QT syndrome (Disputed Evidence), mode of inheritance: AD
• catecholaminergic polymorphic ventricular tachycardia (Disputed Evidence), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Atrial fibrillation, familial 10; Long QT syndrome 3; Idiopathic ventricular fibrillation; Heart block, progressive, type IA; Heart block, nonprogressive; Sick sinus syndrome 1, autosomal recessive; Cardiomyopathy, dilated, 1E; Brugada syndrome 1; Ventricular fibrillation, familial 1	AD/AR/Digenic	Cardiovascular; Pharmacogenomic	In Atrial fibrilliation, medical/preventive management may decrease morbidity; In Sick sinus syndrome, in pediatric patients, treatment of associated exercise intolerance, presyncope or syncope, typically requires lifelong cardiac pacing; For dysrhthymia-related phenotypes, surveillance and preventive/treatment measures (eg, in LQTS3: beta-blockers, pacemakers, or ICD; In CMD1E: permanent pacing is required in most individuals; Brugada syndrome: ICDs) can decrease morbidity/mortality; For progressive/nonprogressive heart block, surveillance can allow timely treatment (eg, with pacemaker); 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	Cardiovascular	3953067; 8541846; 7889574; 9521325; 10590249; 10471492; 10940383; 10911008; 11748104; 11901046; 11823453; 14523039; 12574143; 12522116; 15466643; 15051636; 15671429; 15840476; 16922724; 16453024; 17038146; 18599870; 18378609; 19122847; 18451998; 18503232; 20025708; 20301690
The inheriatance of conditions such as LQTS and Atrial standstill may involve digenic inheritance involving other genes, such as GJA5

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SCN5A gene.

• Brugada syndrome (1917 variants)
• not provided (1571 variants)
• Cardiac arrhythmia (1287 variants)
• Cardiovascular phenotype (908 variants)
• not specified (444 variants)
• Brugada syndrome 1 (314 variants)
• Congenital long QT syndrome (277 variants)
• Long QT syndrome 3 (238 variants)
• 8 conditions (209 variants)
• Dilated cardiomyopathy 1E (200 variants)
• Sick sinus syndrome 1 (195 variants)
• Progressive familial heart block, type 1A (183 variants)
• Ventricular fibrillation, paroxysmal familial, type 1 (182 variants)
• Long QT syndrome (75 variants)
• Cardiomyopathy (68 variants)
• Sick sinus syndrome (39 variants)
• Progressive familial heart block (37 variants)
• Dilated Cardiomyopathy, Dominant (37 variants)
• Paroxysmal familial ventricular fibrillation (37 variants)
• Primary dilated cardiomyopathy (34 variants)
• SCN5A-Related Disorders (18 variants)
• SCN5A-related condition (17 variants)
• Atrial fibrillation, familial, 10 (12 variants)
• SUDDEN INFANT DEATH SYNDROME (11 variants)
• Atrial fibrillation (11 variants)
• Brugada syndrome (shorter-than-normal QT interval) (10 variants)
• Primary familial hypertrophic cardiomyopathy (9 variants)
• Long QT syndrome 3;Brugada syndrome 1 (8 variants)
• Conduction system disorder (7 variants)
• Arrhythmogenic right ventricular cardiomyopathy (6 variants)
• Primary familial dilated cardiomyopathy (6 variants)
• Familial isolated arrhythmogenic right ventricular dysplasia (6 variants)
• Long QT syndrome 3;Brugada syndrome (5 variants)
• Hypertrophic cardiomyopathy (5 variants)
• Brugada syndrome 1;Long QT syndrome 3 (5 variants)
• Inborn genetic diseases (5 variants)
• Ventricular tachycardia (4 variants)
• Death in infancy (3 variants)
• Cardiac arrest (3 variants)
• Long QT syndrome 1 (3 variants)
• Sudden cardiac death (3 variants)
• Left ventricular noncompaction cardiomyopathy (3 variants)
• 7 conditions (2 variants)
• Atrial standstill 1, digenic (2 variants)
• Ventricular fibrillation (2 variants)
• Atrioventricular block (2 variants)
• SCN5A-related disorder (2 variants)
• Acquired long QT syndrome (2 variants)
• Long QT syndrome, drug-associated (2 variants)
• Wolff-Parkinson-White pattern (2 variants)
• Dilated cardiomyopathy 1A (2 variants)
• Sudden cardiac arrest (2 variants)
• Brugada syndrome;Congenital long QT syndrome (2 variants)
• Sudden unexplained death (2 variants)
• 6 conditions (2 variants)
• Conduction disorder of the heart (2 variants)
• Long QT syndrome 3, acquired, susceptibility to (2 variants)
• Brugada syndrome, lidocaine-induced (2 variants)
• Arthrogryposis multiplex congenita;Fetal akinesia deformation sequence 1 (1 variants)
• Pulmonary valve stenosis (rare);Ventricular tachycardia (1 variants)
• Primary dilated cardiomyopathy;Migraine;Hemiplegia (1 variants)
• Dilated cardiomyopathy 1E;Brugada syndrome 1 (1 variants)
• Sinus node disease (1 variants)
• See cases (1 variants)
• SCN5A-related conditions (1 variants)
• SUDDEN INFANT DEATH SYNDROME;Brugada syndrome (1 variants)
• Death in early adulthood (1 variants)
• Prolonged QT interval;Sudden cardiac death (1 variants)
• Brugada syndrome;Long QT syndrome (1 variants)
• Long QT syndrome 3/6, digenic (1 variants)
• Catecholaminergic polymorphic ventricular tachycardia 1 (1 variants)
• Cardiomyopathy;Long QT syndrome (1 variants)
• Brugada syndrome 1;Atrial fibrillation, familial, 10;Long QT syndrome 3;Dilated cardiomyopathy 1E;Ventricular fibrillation, paroxysmal familial, type 1 (1 variants)
• Brugada syndrome;Long QT syndrome 3 (1 variants)
• Primary dilated cardiomyopathy;Brugada syndrome (1 variants)
• Long QT syndrome 2 (1 variants)
• Left ventricular noncompaction 1 (1 variants)
• Syncope (1 variants)
• Torsades de pointes (1 variants)
• Long QT syndrome;Brugada syndrome (1 variants)
• SCN5A-related disease (1 variants)
• Brugada syndrome;Sudden cardiac arrest;Sinus node disease (1 variants)
• AV junctional rhythm (1 variants)
• SCN5A-Related Arrhythmias (1 variants)
• Congenital long QT syndrome;Brugada syndrome (1 variants)
• Atrial fibrillation;Brugada syndrome (1 variants)
• Long QT syndrome 3;Dilated cardiomyopathy 1E (1 variants)
• Long QT syndrome 2/3, digenic (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SCN5A gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	1	1	14	774	2	792
missense	34	67	1469	28		1598
nonsense	74	23	3			100
start loss		1	1			2
frameshift	96	26	11			133
inframe indel	4	2	32			38
splice donor/acceptor (+/-2bp)	11	43	1			55
splice region		2	44	58		104
non coding		3	73	213	65	354
Total	220	166	1604	1015	67

Highest pathogenic variant AF is 0.0000132

Variants in SCN5A

This is a list of pathogenic ClinVar variants found in the SCN5A region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
3-38548172-C-T		Paroxysmal familial ventricular fibrillation • Dilated Cardiomyopathy, Dominant • Progressive familial heart block • Congenital long QT syndrome • Long QT syndrome • Sick sinus syndrome • Brugada syndrome	Uncertain significance (Jun 14, 2016)
3-38548175-T-TCCCTCCTTTTTCCTACTCTCTTCTC		Long QT syndrome • Congenital long QT syndrome • Progressive familial heart block • Brugada syndrome • Dilated Cardiomyopathy, Dominant • Paroxysmal familial ventricular fibrillation • Sick sinus syndrome	Likely benign (Jun 14, 2016)
3-38548186-G-T		Progressive familial heart block, type 1A • Ventricular fibrillation, paroxysmal familial, type 1 • Dilated cardiomyopathy 1E • Congenital long QT syndrome • Brugada syndrome 1 • Sick sinus syndrome 1 • Long QT syndrome 3	Uncertain significance (Jan 13, 2018)
3-38548314-C-T		Dilated cardiomyopathy 1E • Ventricular fibrillation, paroxysmal familial, type 1 • Progressive familial heart block, type 1A • Sick sinus syndrome 1 • Long QT syndrome 3 • Brugada syndrome 1	Uncertain significance (Jan 12, 2018)
3-38548352-G-A		Sick sinus syndrome • Long QT syndrome • Brugada syndrome • Progressive familial heart block • Dilated Cardiomyopathy, Dominant • Paroxysmal familial ventricular fibrillation • Congenital long QT syndrome	Uncertain significance (Jun 14, 2016)
3-38548378-G-T		Long QT syndrome • Dilated Cardiomyopathy, Dominant • Progressive familial heart block • Congenital long QT syndrome • Brugada syndrome • Paroxysmal familial ventricular fibrillation • Sick sinus syndrome	Uncertain significance (Jun 14, 2016)
3-38548389-G-A		Brugada syndrome 1 • Ventricular fibrillation, paroxysmal familial, type 1 • Progressive familial heart block, type 1A • Congenital long QT syndrome • Long QT syndrome 3 • Dilated cardiomyopathy 1E • Sick sinus syndrome 1	Uncertain significance (Jan 13, 2018)
3-38548437-C-T		Brugada syndrome 1 • Progressive familial heart block, type 1A • Long QT syndrome 3 • Ventricular fibrillation, paroxysmal familial, type 1 • Sick sinus syndrome 1 • Dilated cardiomyopathy 1E	Benign/Likely benign (Jan 12, 2018)
3-38548478-A-C		Progressive familial heart block, type 1A • Dilated cardiomyopathy 1E • Long QT syndrome 3 • Brugada syndrome 1 • Ventricular fibrillation, paroxysmal familial, type 1 • Sick sinus syndrome 1	Uncertain significance (Jan 13, 2018)
3-38548485-T-A		Long QT syndrome • Brugada syndrome • Dilated Cardiomyopathy, Dominant • Sick sinus syndrome • Congenital long QT syndrome • Paroxysmal familial ventricular fibrillation • Progressive familial heart block	Uncertain significance (Jun 14, 2016)
3-38548501-G-C		Brugada syndrome 1 • Progressive familial heart block, type 1A • Ventricular fibrillation, paroxysmal familial, type 1 • Sick sinus syndrome 1 • Long QT syndrome 3 • Dilated cardiomyopathy 1E	Conflicting classifications of pathogenicity (Jan 13, 2018)
3-38548519-C-T		Progressive familial heart block, type 1A • Brugada syndrome 1 • Sick sinus syndrome 1 • Dilated cardiomyopathy 1E • Ventricular fibrillation, paroxysmal familial, type 1 • Long QT syndrome 3	Uncertain significance (Jan 13, 2018)
3-38548577-G-C		Progressive familial heart block • Paroxysmal familial ventricular fibrillation • Brugada syndrome • Dilated Cardiomyopathy, Dominant • Sick sinus syndrome • Long QT syndrome • Congenital long QT syndrome	Uncertain significance (Jun 14, 2016)
3-38548578-C-T		Ventricular fibrillation, paroxysmal familial, type 1 • Progressive familial heart block, type 1A • Dilated cardiomyopathy 1E • Long QT syndrome 3 • Brugada syndrome 1 • Sick sinus syndrome 1	Uncertain significance (Jan 13, 2018)
3-38548590-C-G		Dilated Cardiomyopathy, Dominant • Long QT syndrome • Brugada syndrome • Progressive familial heart block • Congenital long QT syndrome • Sick sinus syndrome • Paroxysmal familial ventricular fibrillation	Uncertain significance (Jun 14, 2016)
3-38548616-G-A		Long QT syndrome • Progressive familial heart block • Congenital long QT syndrome • Sick sinus syndrome • Dilated Cardiomyopathy, Dominant • Brugada syndrome • Paroxysmal familial ventricular fibrillation	Uncertain significance (Jun 14, 2016)
3-38548620-C-A		Paroxysmal familial ventricular fibrillation • Long QT syndrome • Congenital long QT syndrome • Sick sinus syndrome • Dilated Cardiomyopathy, Dominant • Progressive familial heart block • Brugada syndrome	Uncertain significance (Jun 14, 2016)
3-38548630-C-A		Progressive familial heart block • Paroxysmal familial ventricular fibrillation • Dilated Cardiomyopathy, Dominant • Brugada syndrome • Sick sinus syndrome • Long QT syndrome • Congenital long QT syndrome	Uncertain significance (Jun 14, 2016)
3-38548648-G-A		Progressive familial heart block • Long QT syndrome • Sick sinus syndrome • Paroxysmal familial ventricular fibrillation • Brugada syndrome • Congenital long QT syndrome • Dilated Cardiomyopathy, Dominant	Uncertain significance (Jun 14, 2016)
3-38548719-C-A		Dilated Cardiomyopathy, Dominant • Sick sinus syndrome • Congenital long QT syndrome • Paroxysmal familial ventricular fibrillation • Long QT syndrome • Progressive familial heart block • Brugada syndrome	Uncertain significance (Jun 14, 2016)
3-38548753-C-G		Brugada syndrome 1 • Congenital long QT syndrome • Ventricular fibrillation, paroxysmal familial, type 1 • Dilated cardiomyopathy 1E • Sick sinus syndrome 1 • Progressive familial heart block, type 1A • Long QT syndrome 3	Uncertain significance (Jan 12, 2018)
3-38548766-G-A		Long QT syndrome 3 • Dilated cardiomyopathy 1E • Progressive familial heart block, type 1A • Ventricular fibrillation, paroxysmal familial, type 1 • Sick sinus syndrome 1 • Brugada syndrome 1	Uncertain significance (Jan 13, 2018)
3-38548784-A-G		Sick sinus syndrome 1 • Dilated cardiomyopathy 1E • Long QT syndrome 3 • Progressive familial heart block, type 1A • Brugada syndrome 1 • Congenital long QT syndrome • Ventricular fibrillation, paroxysmal familial, type 1	Benign/Likely benign (May 16, 2021)
3-38548825-A-C		Dilated cardiomyopathy 1E • Progressive familial heart block, type 1A • Long QT syndrome 3 • Congenital long QT syndrome • Sick sinus syndrome 1 • Brugada syndrome 1 • Ventricular fibrillation, paroxysmal familial, type 1	Conflicting classifications of pathogenicity (May 22, 2021)
3-38548867-C-CT		Progressive familial heart block • Brugada syndrome • Paroxysmal familial ventricular fibrillation • Sick sinus syndrome • Congenital long QT syndrome • Dilated Cardiomyopathy, Dominant • Long QT syndrome	Benign/Likely benign (May 14, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SCN5A	protein_coding	protein_coding	ENST00000413689	27	101617

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.913	0.0871	125681	0	67	125748	0.000266

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.75	967	1.24e+3	0.780	0.0000791	13275
Missense in Polyphen		452	672.62	0.672		7415
Synonymous	0.342	503	513	0.981	0.0000356	4001
Loss of Function	6.70	17	82.8	0.205	0.00000451	899

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000423	0.000416
Ashkenazi Jewish	0.000101	0.0000992
East Asian	0.0000558	0.0000544
Finnish	0.00103	0.00102
European (Non-Finnish)	0.000226	0.000220
Middle Eastern	0.0000558	0.0000544
South Asian	0.000137	0.000131
Other	0.000329	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient (PubMed:1309946, PubMed:21447824, PubMed:25370050, PubMed:23420830, PubMed:23085483, PubMed:26279430, PubMed:26392562, PubMed:26776555). It is a tetrodotoxin-resistant Na(+) channel isoform (PubMed:1309946). This channel is responsible for the initial upstroke of the action potential. Channel inactivation is regulated by intracellular calcium levels (PubMed:19074138). {ECO:0000269|PubMed:1309946, ECO:0000269|PubMed:19074138, ECO:0000269|PubMed:21447824, ECO:0000269|PubMed:23085483, ECO:0000269|PubMed:23420830, ECO:0000269|PubMed:24167619, ECO:0000269|PubMed:25370050, ECO:0000269|PubMed:26279430, ECO:0000269|PubMed:26392562, ECO:0000269|PubMed:26776555}.
• Disease: DISEASE: Progressive familial heart block 1A (PFHB1A) [MIM:113900]: A cardiac bundle branch disorder characterized by progressive alteration of cardiac conduction through the His- Purkinje system, with a pattern of a right bundle-branch block and/or left anterior hemiblock occurring individually or together. It leads to complete atrio-ventricular block causing syncope and sudden death. {ECO:0000269|PubMed:11234013, ECO:0000269|PubMed:11804990, ECO:0000269|PubMed:12569159, ECO:0000269|PubMed:12574143, ECO:0000269|PubMed:19251209, ECO:0000269|PubMed:23420830}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Long QT syndrome 3 (LQT3) [MIM:603830]: A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. {ECO:0000269|PubMed:10377081, ECO:0000269|PubMed:10508990, ECO:0000269|PubMed:10590249, ECO:0000269|PubMed:10627139, ECO:0000269|PubMed:10911008, ECO:0000269|PubMed:10973849, ECO:0000269|PubMed:11304498, ECO:0000269|PubMed:11410597, ECO:0000269|PubMed:11710892, ECO:0000269|PubMed:11889015, ECO:0000269|PubMed:11997281, ECO:0000269|PubMed:12209021, ECO:0000269|PubMed:12454206, ECO:0000269|PubMed:12673799, ECO:0000269|PubMed:15840476, ECO:0000269|PubMed:16414944, ECO:0000269|PubMed:16922724, ECO:0000269|PubMed:18060054, ECO:0000269|PubMed:18451998, ECO:0000269|PubMed:18708744, ECO:0000269|PubMed:18848812, ECO:0000269|PubMed:18929331, ECO:0000269|PubMed:19716085, ECO:0000269|PubMed:26392562, ECO:0000269|PubMed:7651517, ECO:0000269|PubMed:7889574, ECO:0000269|PubMed:8541846, ECO:0000269|PubMed:9506831, ECO:0000269|PubMed:9686753, ECO:0000269|Ref.35}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Brugada syndrome 1 (BRGDA1) [MIM:601144]: 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:10532948, ECO:0000269|PubMed:10618304, ECO:0000269|PubMed:10690282, ECO:0000269|PubMed:11410597, ECO:0000269|PubMed:11748104, ECO:0000269|PubMed:11823453, ECO:0000269|PubMed:11901046, ECO:0000269|PubMed:12051963, ECO:0000269|PubMed:12106943, ECO:0000269|PubMed:15023552, ECO:0000269|PubMed:15338453, ECO:0000269|PubMed:15579534, ECO:0000269|PubMed:15851320, ECO:0000269|PubMed:16266370, ECO:0000269|PubMed:16325048, ECO:0000269|PubMed:16616735, ECO:0000269|PubMed:17075016, ECO:0000269|PubMed:17081365, ECO:0000269|PubMed:17198989, ECO:0000269|PubMed:18252757, ECO:0000269|PubMed:18341814, ECO:0000269|PubMed:18451998, ECO:0000269|PubMed:18456723, ECO:0000269|PubMed:18616619, ECO:0000269|PubMed:19251209, ECO:0000269|PubMed:19272188, ECO:0000269|PubMed:20129283, ECO:0000269|PubMed:23085483, ECO:0000269|PubMed:23420830, ECO:0000269|PubMed:24167619, ECO:0000269|PubMed:26279430, ECO:0000269|PubMed:26776555, ECO:0000269|PubMed:9521325}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Sick sinus syndrome 1 (SSS1) [MIM:608567]: The term 'sick sinus syndrome' encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors. SSS1 onset is in utero, infancy, or early childhood. {ECO:0000269|PubMed:11748104, ECO:0000269|PubMed:14523039, ECO:0000269|PubMed:22795782}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Familial paroxysmal ventricular fibrillation 1 (VF1) [MIM:603829]: A cardiac arrhythmia marked by fibrillary contractions of the ventricular muscle due to rapid repetitive excitation of myocardial fibers without coordinated contraction of the ventricle and by absence of atrial activity. {ECO:0000269|PubMed:10940383}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Sudden infant death syndrome (SIDS) [MIM:272120]: SIDS is the sudden death of an infant younger than 1 year that remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of clinical history. Pathophysiologic mechanisms for SIDS may include respiratory dysfunction, cardiac dysrhythmias, cardiorespiratory instability, and inborn errors of metabolism, but definitive pathogenic mechanisms precipitating an infant sudden death remain elusive. {ECO:0000269|PubMed:18596570, ECO:0000269|PubMed:19302788}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Atrial standstill 1 (ATRST1) [MIM:108770]: A rare arrhythmia characterized by the absence of electrical and mechanical activity in the atria. Electrocardiographically, it is characterized by bradycardia, the absence of P waves, and a junctional narrow complex escape rhythm. {ECO:0000269|PubMed:12522116, ECO:0000269|PubMed:23420830}. Note=The disease may be caused by mutations affecting distinct genetic loci, including the gene represented in this entry. A mutation in SCN5A has been detected in combination with a rare GJA5 genotype in a large family with atrial standstill.; DISEASE: Cardiomyopathy, dilated 1E (CMD1E) [MIM:601154]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:15466643, ECO:0000269|PubMed:23420830}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Atrial fibrillation, familial, 10 (ATFB10) [MIM:614022]: 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:18088563, ECO:0000269|PubMed:18378609}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Adrenergic signaling in cardiomyocytes - Homo sapiens (human);Antiarrhythmic Pathway, Pharmacodynamics;Disopyramide Action Pathway;Procainamide (Antiarrhythmic) Action Pathway;Phenytoin (Antiarrhythmic) Action Pathway;Fosphenytoin (Antiarrhythmic) Action Pathway;Bopindolol Action Pathway;Timolol Action Pathway;Carteolol Action Pathway;Bevantolol Action Pathway;Practolol Action Pathway;Dobutamine Action Pathway;Isoprenaline Action Pathway;Arbutamine Action Pathway;Amiodarone Action Pathway;Levobunolol Action Pathway;Metipranolol Action Pathway;Mexiletine Action Pathway;Lidocaine (Antiarrhythmic) Action Pathway;Quinidine Action Pathway;Sotalol Action Pathway;Epinephrine Action Pathway;Betaxolol Action Pathway;Atenolol Action Pathway;Alprenolol Action Pathway;Acebutolol Action Pathway;Muscle/Heart Contraction;Diltiazem Action Pathway;Propranolol Action Pathway;Pindolol Action Pathway;Penbutolol Action Pathway;Oxprenolol Action Pathway;Metoprolol Action Pathway;Esmolol Action Pathway;Bisoprolol Action Pathway;Bupranolol Action Pathway;Nebivolol Action Pathway;Amlodipine Action Pathway;Verapamil Action Pathway;Nitrendipine Action Pathway;Nisoldipine Action Pathway;Nimodipine Action Pathway;Ibutilide Action Pathway;Tocainide Action Pathway;Flecainide Action Pathway;Isradipine Action Pathway;Fosphenytoin (Antiarrhythmic) Metabolism Pathway;Nifedipine Action Pathway;Felodipine Action Pathway;Nadolol Action Pathway;Carvedilol Action Pathway;Labetalol Action Pathway;Cardiac Progenitor Differentiation;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Developmental Biology;Phase 0 - rapid depolarisation;Cardiac conduction;Muscle contraction;Interaction between L1 and Ankyrins;L1CAM interactions;Axon guidance (Consensus)

Recessive Scores

• pRec: 0.258

Intolerance Scores

• loftool: 0.000413
• rvis_EVS: -1.88
• rvis_percentile_EVS: 1.99

Haploinsufficiency Scores

• pHI: 0.273
• hipred: Y
• hipred_score: 0.711
• ghis: 0.452

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.694

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Scn5a
• Phenotype: growth/size/body region phenotype; muscle phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan)

Gene ontology

• Biological process: regulation of heart rate;cardiac ventricle development;brainstem development;sodium ion transport;positive regulation of sodium ion transport;response to denervation involved in regulation of muscle adaptation;neuronal action potential;telencephalon development;cerebellum development;sodium ion transmembrane transport;odontogenesis of dentin-containing tooth;positive regulation of action potential;positive regulation of epithelial cell proliferation;membrane depolarization;cardiac muscle contraction;regulation of ventricular cardiac muscle cell membrane repolarization;regulation of atrial cardiac muscle cell membrane depolarization;regulation of atrial cardiac muscle cell membrane repolarization;regulation of ventricular cardiac muscle cell membrane depolarization;cellular response to calcium ion;cardiac muscle cell action potential involved in contraction;regulation of cardiac muscle cell contraction;ventricular cardiac muscle cell action potential;membrane depolarization during action potential;membrane depolarization during cardiac muscle cell action potential;atrial cardiac muscle cell action potential;SA node cell action potential;AV node cell action potential;bundle of His cell action potential;membrane depolarization during AV node cell action potential;membrane depolarization during SA node cell action potential;membrane depolarization during Purkinje myocyte cell action potential;membrane depolarization during bundle of His cell action potential;AV node cell to bundle of His cell communication;regulation of heart rate by cardiac conduction;membrane depolarization during atrial cardiac muscle cell action potential;regulation of sodium ion transmembrane transport
• Cellular component: voltage-gated sodium channel complex;endoplasmic reticulum;plasma membrane;caveola;cell surface;intercalated disc;integral component of membrane;lateral plasma membrane;Z disc;T-tubule;axon;sarcolemma;perinuclear region of cytoplasm
• Molecular function: voltage-gated ion channel activity;voltage-gated sodium channel activity;protein binding;calmodulin binding;fibroblast growth factor binding;enzyme binding;protein kinase binding;protein domain specific binding;ankyrin binding;ubiquitin protein ligase binding;ion channel binding;nitric-oxide synthase binding;voltage-gated sodium channel activity involved in cardiac muscle cell action potential;voltage-gated sodium channel activity involved in AV node cell action potential;voltage-gated sodium channel activity involved in bundle of His cell action potential;voltage-gated sodium channel activity involved in Purkinje myocyte action potential;voltage-gated sodium channel activity involved in SA node cell action potential;scaffold protein binding