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SCN5A
sodium voltage-gated channel alpha subunit 5
The SCN5A gene provides instructions for creating a crucial component of sodium channels, which are essential for the heart's electrical signalling and rhythm. SCN5A encodes the alpha subunit of a voltage-gated sodium channel, predominantly found in cardiac muscle cells.
SCN5A is located on the short (p) arm of chromosome 3, at band 3p22.2. Arm ratio per GRCh38 - banding schematic.
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The SCN5A gene, or sodium voltage-gated channel alpha subunit 5, is critical for normal heart function. It contains the genetic blueprint for a protein that forms part of voltage-gated sodium channels, particularly abundant in the heart's muscle cells. These channels are integral to the heart's electrical system, controlling the flow of sodium ions into cells, which in turn generates and transmits electrical signals across the cardiac tissue. Proper function of the SCN5A-encoded protein ensures the synchronised contraction of heart chambers and helps maintain a stable heart rhythm.
Pathogenic variants within SCN5A are linked to a spectrum of inherited cardiac conditions. These conditions often involve disturbances in the heart's electrical activity, known as arrhythmias, which can range in severity. Understanding the role of SCN5A is therefore crucial for diagnosing and managing these complex heart disorders.
What the gene does
The SCN5A gene is responsible for synthesising the alpha subunit of the cardiac voltage-gated sodium channel, Nav1.5. This protein is a central component of ion channels embedded in the membranes of heart muscle cells, known as cardiomyocytes. These channels regulate the rapid influx of positively charged sodium ions into the cell, a process fundamental to the initiation and propagation of electrical impulses that trigger heartbeats.
Specifically, the Nav1.5 channel opens and closes in a highly regulated manner, allowing sodium ions to rush into the cell and depolarise the cell membrane. This rapid depolarisation creates the action potential, which is the electrical signal that spreads throughout the heart, coordinating its contractions. The channels facilitate the rapid upstroke phase of the cardiac action potential, which is crucial for the efficient and synchronous contraction of the atria and ventricles.
Dysregulation of sodium ion flow due to SCN5A variants can have significant consequences. For instance, some variants may lead to a reduction or loss of channel function, impeding the flow of sodium ions. This can slow down electrical conduction, prolong the repolarisation phase, or interfere with pacemaker activity, contributing to conditions like Brugada syndrome or progressive cardiac conduction defects. Conversely, other variants might cause the channel to remain open for too long or to reopen too easily, resulting in an abnormal gain of function. This can lead to prolonged depolarisation and increased excitability, as seen in certain forms of Long QT syndrome.
The SCN5A protein also interacts with other cellular components, including fibroblast growth factor 13 (FGF13) and ubiquitin ligases like NEDD4, NEDD4L, and WWP2. These interactions can modulate the channel's expression, localisation, and degradation, further influencing its overall function and contributing to the complexity of cardiac electrical regulation.
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Chromosome location
The SCN5A gene is located on chromosome 3, specifically at position 3p22.2. This genomic address describes its precise location on the short arm (p) of chromosome 3, within band 22.2. The SCN5A gene encodes a protein that is 2016 amino acids long.
Protein structure
The SCN5A protein is a large, complex polypeptide comprising 2016 amino acids, serving as the alpha subunit of a voltage-gated sodium channel. Its structure includes several key domains crucial for its function. The protein features multiple disordered regions: one near the N-terminus from amino acids 28-56, another from amino acids 461-591, a third from amino acids 1005-1141, and a final one towards the C-terminus from amino acids 1959-2016. These disordered regions often play roles in protein-protein interactions or provide flexibility.
The core functional architecture is defined by four repetitive domains, labelled I, II, III, and IV. Repeat I spans amino acids 113-420, Repeat II from amino acids 699-969, Repeat III from amino acids 1187-1501, and Repeat IV from amino acids 1510-1807. These repeats typically contain transmembrane segments that form the ion-conducting pore and voltage-sensing elements of the channel. Towards the C-terminal end, specific interaction domains are present: an interaction region with FGF13 from amino acids 1839-1901, and an IQ domain from amino acids 1901-1930. Additionally, a region involved in interaction with NEDD4, NEDD4L, and WWP2 is located at amino acids 1974-1977, which suggests a role in ubiquitination and channel degradation or trafficking.
Key variants
Variants in the SCN5A gene encompass a wide range of genetic changes that can impact the structure and function of the cardiac sodium channel protein. These variants can include single nucleotide changes (missense, nonsense, or splice site variants), as well as small insertions or deletions. Depending on their nature and location, SCN5A variants can lead to either a gain or loss of function in the sodium channel, or alter its kinetics, ultimately disrupting the heart's electrical stability. The clinical consequences of these variants are highly variable, ranging from mild symptoms to severe, life-threatening cardiac arrhythmias.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.102_103del | p.Gly35fs | Pathogenic | ★★☆☆ | not provided |
c.1024dup | p.Leu342fs | Pathogenic | ★★☆☆ | Cardiovascular phenotype |
c.1051_1058dup | p.Ser354fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1058C>T | p.Thr353Ile | Pathogenic/Likely pathogenic | ★★☆☆ | Brugada syndrome |
c.1066G>A | p.Asp356Asn | Pathogenic/Likely pathogenic | ★★☆☆ | Brugada syndrome |
c.1080G>A | p.Trp360Ter | Pathogenic | ★★☆☆ | not provided |
c.1099C>T | p.Arg367Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital long QT syndrome |
c.1100G>A | p.Arg367His | Pathogenic | ★★☆☆ | Brugada syndrome 1 |
c.1111C>T | p.Gln371Ter | Pathogenic | ★★☆☆ | Cardiac arrhythmia |
c.1120T>G | p.Trp374Gly | Pathogenic/Likely pathogenic | ★★☆☆ | Brugada syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the SCN5A gene are associated with several inherited cardiac conditions, primarily affecting the heart's electrical conduction system. These conditions are inherited in an autosomal dominant (AD) manner, meaning only one copy of an altered gene is sufficient to cause the condition. Key conditions linked to SCN5A include Brugada syndrome, characterised by distinctive electrocardiogram patterns and an increased risk of sudden cardiac arrest. Another associated condition is Long QT syndrome type 3, which involves a prolonged repolarisation phase of the heart's electrical cycle, predisposing individuals to specific arrhythmias. SCN5A variants also contribute to Progressive cardiac conduction defect (Lenègre), a condition where the heart's electrical conduction progressively slows down.
Inheritance pattern
Conditions caused by pathogenic SCN5A variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
SCN5A is a gene of significant clinical interest within the UK National Health Service (NHS) Genomic Medicine Service. It is included on several green-rated PanelApp panels, indicating that there is strong evidence for its association with specific conditions and that genes on these panels are routinely analysed in NHS genetic testing. This includes the Brugada syndrome and cardiac sodium channel disease panel (R128), Dilated and arrhythmogenic cardiomyopathy panel (R132), Dilated Cardiomyopathy and conduction defects panel, Foetal anomalies panel (R21), Long QT syndrome panel (R127), Paediatric or syndromic cardiomyopathy panel (R135), and Progressive cardiac conduction disease panel (R328).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a heart-healthy lifestyle is often recommended for individuals at risk of, or diagnosed with, inherited cardiac conditions, including those associated with SCN5A variants. Research suggests that general lifestyle factors can influence overall cardiovascular health, although specific evidence directly linking them to the progression or severity of SCN5A-related conditions is still evolving. For example, a balanced diet rich in fruits, vegetables, and whole grains, and low in saturated and trans fats, may support cardiovascular well-being in the general population. Regular physical activity, appropriate for an individual's health status and under medical guidance, is also generally beneficial for heart health. Avoiding excessive alcohol intake and refraining from smoking are widely recognised as important for reducing cardiovascular risk. It is important for individuals with SCN5A variants to discuss any lifestyle changes with their healthcare provider, especially regarding exercise, as certain activities might need to be modified based on their specific condition and risk profile.
Supplement considerations
There is currently no conclusive scientific evidence to suggest that specific dietary supplements can prevent or treat inherited cardiac conditions associated with SCN5A variants. Research into the effects of various supplements on cardiovascular health is ongoing, but definitive clinical recommendations are limited. For example, some studies investigate the role of omega-3 fatty acids in general heart health, but their specific impact on SCN5A-related arrhythmias remains unproven. Similarly, while antioxidants are often promoted for their potential benefits, there is no robust evidence they can mitigate the effects of SCN5A variants. Individuals should always consult with a healthcare professional before starting any new supplement regimen, especially if they have a diagnosed SCN5A-related condition, as some supplements may interact with medications or have unforeseen effects on cardiac function.
Frequently asked questions
What is the SCN5A gene?
The SCN5A gene provides instructions for making the alpha subunit of a voltage-gated sodium channel, primarily found in heart muscle cells. This protein is crucial for generating and transmitting the electrical signals that regulate heartbeats and rhythm.
What conditions are associated with SCN5A variants?
Variants in SCN5A are associated with several inherited cardiac conditions, including Brugada syndrome, Long QT syndrome type 3, and Progressive cardiac conduction defect (Lenègre). These conditions can cause abnormal heart rhythms (arrhythmias).
How are SCN5A-related conditions inherited?
Conditions linked to SCN5A variants are typically inherited in an autosomal dominant pattern. This means that an individual needs to inherit only one copy of the altered gene to be at risk of developing the condition.
What does a cardiac sodium channel do?
A cardiac sodium channel, partly formed by the SCN5A protein, controls the flow of sodium ions into heart cells. This ion movement creates electrical impulses that initiate and coordinate the contractions of the heart chambers.
Is the SCN5A gene tested in the UK NHS?
Yes, the SCN5A gene is included on several NHS PanelApp panels, such as those for Brugada syndrome, Long QT syndrome, and various forms of cardiomyopathy, indicating its importance in clinical genetic testing within the UK.
Can lifestyle changes help with SCN5A-related conditions?
While a heart-healthy lifestyle is generally recommended, there is no conclusive evidence that specific lifestyle changes can prevent or treat SCN5A-related conditions. Any modifications should be discussed with a healthcare professional.
References
- Brugada P. Brugada syndrome: More than 20 years of scientific excitement. Journal of cardiology. 2016. PMID: 26627541
- Zaklyazminskaya E, Dzemeshkevich S. The role of mutations in the SCN5A gene in cardiomyopathies. Biochimica et biophysica acta. 2016. PMID: 26916278
- Veerman CC, Wilde AA, Lodder EM. The cardiac sodium channel gene SCN5A and its gene product NaV1.5: Role in physiology and pathophysiology. Gene. 2015. PMID: 26361848
- Kapplinger JD, Tester DJ, Alders M. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart rhythm. 2010. PMID: 20129283
- Butters TD, Aslanidi OV, Inada S. Mechanistic links between Na+ channel (SCN5A) mutations and impaired cardiac pacemaking in sick sinus syndrome. Circulation research. 2010. PMID: 20448214
- Gui J, Wang T, Jones RP. Multiple loss-of-function mechanisms contribute to SCN5A-related familial sick sinus syndrome. PloS one. 2010. PMID: 20539757
- Lei M, Huang CL, Zhang Y. Genetic Na+ channelopathies and sinus node dysfunction. Progress in biophysics and molecular biology. 2008. PMID: 19027778
- Plant LD, Bowers PN, Liu Q. A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y. The Journal of clinical investigation. 2006. PMID: 16453024
- Shimizu W, Aiba T, Kamakura S. Mechanisms of disease: current understanding and future challenges in Brugada syndrome. Nature clinical practice. Cardiovascular medicine. 2005. PMID: 16119703
- Paulussen AD, Gilissen RA, Armstrong M. Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients. Journal of molecular medicine (Berlin, Germany). 2004. PMID: 14760488
- Herfst LJ, Rook MB, Jongsma HJ. Trafficking and functional expression of cardiac Na+ channels. Journal of molecular and cellular cardiology. 2004. PMID: 14871545
- Juang JM, Huang SK. Brugada syndrome--an under-recognized electrical disease in patients with sudden cardiac death. Cardiology. 2004. PMID: 14967959
- Vatta M, Dumaine R, Varghese G. Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome. Human molecular genetics. 2002. PMID: 11823453
- Yang P, Kanki H, Drolet B. Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation. 2002. PMID: 11997281