Gene "SCN5A"
Found 18 records
Gene information
Gene symbol:
SCN5A
See related:
Ensembl: ENSG00000183873, Gene ID: 6331
Additive variants :
Undetected
Genetic interaction partners
No data
Modifier statisitcs
Record:
18
Disorder:
4
Vriant:
12
Reference:
7
Effect type:
Expressivity(16)
,Penetrance(2)
Modifier effect:
Altered severity(9)
,Risk factor(6)
,Altered incidence(2)
,Altered gene activity(1)
Details:
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Variant 1:Gene:Genomic location:dbSNP ID:Target disease:Brugada Syndrome(DOID_0050451)Effect type:ExpressivityModifier effect:Altered severityEvidence:From review articleEffect:Individuals with the mutation present with a more severe phenotype including spontaneous atrial tachyarrhythmia at young age.Reference:Title:Reduced Penetrance and Variable Expression of SCN5A Mutations and the Importance of Co-inherited Genetic Variants: Case Report and Review of the Literature.Species studied:HumanAbstract:Mutations in the SCN5A gene are responsible for multiple phenotypical presentations including Brugada syndrome, long QT syndrome, progressive familial heart block, sick sinus syndrome, dilated cardiomyopathy, lone atrial fibrillation and multiple overlap syndromes. These different phenotypic expressions of a mutation in a single gene can be explained by variable expression and reduced penetrance. One of the possible explanations of these phenomena is the co-inheritance of genetic variants. We describe a family where the individuals exhibit a compound heterozygosity in the SCN5A gene including a mutation (R1632H) and a new variant (M858L). Individuals with both the mutation and new variant present with a more severe phenotype including spontaneous atrial tachyarrhythmia at young age. We give an overview of the different phenotypes of SCN5A disease and discuss the importance of co-inherited genetic variants in the expression of SCN5A disease.
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Variant 2:Gene:Genomic location:dbSNP ID:Target disease:Long QT Syndrome(DOID_2843)Effect type:ExpressivityModifier effect:Risk factorEvidence:From review articleEffect:Risk factorReference:Title:Identification of a KCNQ1 polymorphism acting as a protective modifier against arrhythmic risk in long-QT syndrome.Species studied:HumanAbstract:Long-QT syndrome (LQTS) is characterized by such striking clinical heterogeneity that, even among family members carrying the same mutation, clinical outcome can range between sudden death and no symptoms. We investigated the role of genetic variants as modifiers of risk for cardiac events in patients with LQTS.
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Variant 3:Gene:Genomic location:chr3:38651314dbSNP ID:Target disease:Arrhythmia(HP:0011675)Effect type:ExpressivityModifier effect:Altered severityEvidence:From review articleEffect:SCN5A may also account for more severe phenotypic manifestations in conduction disease31 and Brugada syndrome,may exacerbate or alleviate the severity of the disease.Reference:Title:The primary arrhythmia syndromes: same mutation, different manifestations. Are we starting to understand whySpecies studied:HumanAbstract:The discovery of pathogenic mutations primarily in genes encoding cardiac ion-channel proteins underlying the primary cardiac arrhythmia syndromes has had a remarkable impact on the management of these disorders, especially in patients with the long-QT syndrome. The availability of a genetic diagnostic test has added an important diagnostic tool, providing new opportunities for patient management such as early (presymptomatic) identification and treatment of patients at risk of developing fatal arrhythmias, risk stratification, and installation of gene-specific therapy. However, the fact that the identification of the causal mutation within a family allows diagnosis in other family members independently from the ECG features and arrhythmic manifestations quickly led to the recognition that extensive variability in clinical manifestations (e.g., extent of ECG abnormality and/or symptomatology) may be observed among family members carrying an identical mutation in a single ion channel gene. It is commonly held that this clinical variability stems from interactions between environmental and genetic modifiers with the particular pathogenic mutation. This Molecular Perspectives article reviews current knowledge on these modifiers of disease expression in the cardiac arrhythmia syndromes with particular reference to genetic modifiers.
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Variant 4:Gene:Genomic location:chr3:38592012dbSNP ID:Target disease:Arrhythmia(HP:0011675)Effect type:ExpressivityModifier effect:Risk factorEvidence:From review articleEffect:This genetic variance may contribute as a second genetic modifier for arrhythmia development is under current investigation.Reference:Title:Susceptibility genes and modifiers for cardiac arrhythmias.Species studied:HumanAbstract:The last decade has seen a dramatic increase in the understanding of the molecular basis of arrhythmias. Much of this new information has been driven by genetic studies that focused on rare, monogenic arrhythmia syndromes that were accompanied or followed by cellular electrophysiological or biochemical studies. The marked clinical heterogeneity known from these familial arrhythmia syndromes has led to the development of a multifactorial (multi-hit) concept of arrhythmogenesis in which causal gene mutations have a major effect on disease expression that is further modified by other factors such as age, gender, sympathetic tone, and environmental triggers. Systematic genetic studies have unraveled an unexpected DNA sequence variance in these arrhythmia genes that has ethnic-specific patterns. Whether this genetic variance may contribute as a second genetic modifier for arrhythmia development is under current investigation. The aim of this article is to review common genetic variation in ion channel genes and to compare these recent findings.
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Variant 5:Gene:Genomic location:dbSNP ID:Target disease:Arrhythmia(HP:0011675)Effect type:ExpressivityModifier effect:Altered severityEvidence:From review articleEffect:SCN5A may also account for more severe phenotypic manifestations in conduction disease31 and Brugada syndrome,may exacerbate or alleviate the severity of the disease.Reference:Title:The primary arrhythmia syndromes: same mutation, different manifestations. Are we starting to understand whySpecies studied:HumanAbstract:The discovery of pathogenic mutations primarily in genes encoding cardiac ion-channel proteins underlying the primary cardiac arrhythmia syndromes has had a remarkable impact on the management of these disorders, especially in patients with the long-QT syndrome. The availability of a genetic diagnostic test has added an important diagnostic tool, providing new opportunities for patient management such as early (presymptomatic) identification and treatment of patients at risk of developing fatal arrhythmias, risk stratification, and installation of gene-specific therapy. However, the fact that the identification of the causal mutation within a family allows diagnosis in other family members independently from the ECG features and arrhythmic manifestations quickly led to the recognition that extensive variability in clinical manifestations (e.g., extent of ECG abnormality and/or symptomatology) may be observed among family members carrying an identical mutation in a single ion channel gene. It is commonly held that this clinical variability stems from interactions between environmental and genetic modifiers with the particular pathogenic mutation. This Molecular Perspectives article reviews current knowledge on these modifiers of disease expression in the cardiac arrhythmia syndromes with particular reference to genetic modifiers.
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Variant 6:Gene:Genomic location:chr3:38607917dbSNP ID:Target disease:Arrhythmia(HP:0011675)Effect type:ExpressivityModifier effect:Altered severityEvidence:From review articleEffect:SCN5A may also account for more severe phenotypic manifestations in conduction disease31 and Brugada syndrome,may exacerbate or alleviate the severity of the disease.Reference:Title:The primary arrhythmia syndromes: same mutation, different manifestations. Are we starting to understand whySpecies studied:HumanAbstract:The discovery of pathogenic mutations primarily in genes encoding cardiac ion-channel proteins underlying the primary cardiac arrhythmia syndromes has had a remarkable impact on the management of these disorders, especially in patients with the long-QT syndrome. The availability of a genetic diagnostic test has added an important diagnostic tool, providing new opportunities for patient management such as early (presymptomatic) identification and treatment of patients at risk of developing fatal arrhythmias, risk stratification, and installation of gene-specific therapy. However, the fact that the identification of the causal mutation within a family allows diagnosis in other family members independently from the ECG features and arrhythmic manifestations quickly led to the recognition that extensive variability in clinical manifestations (e.g., extent of ECG abnormality and/or symptomatology) may be observed among family members carrying an identical mutation in a single ion channel gene. It is commonly held that this clinical variability stems from interactions between environmental and genetic modifiers with the particular pathogenic mutation. This Molecular Perspectives article reviews current knowledge on these modifiers of disease expression in the cardiac arrhythmia syndromes with particular reference to genetic modifiers.
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Variant 7:Gene:Genomic location:chr3:38620907dbSNP ID:Alias:SCN5A:S1103YTarget disease:Arrhythmia(HP:0011675)Effect type:ExpressivityModifier effect:Altered severityEvidence:From review articleEffect:SCN5A may also account for more severe phenotypic manifestations in conduction disease31 and Brugada syndrome,may exacerbate or alleviate the severity of the disease.Reference:Title:The primary arrhythmia syndromes: same mutation, different manifestations. Are we starting to understand whySpecies studied:HumanAbstract:The discovery of pathogenic mutations primarily in genes encoding cardiac ion-channel proteins underlying the primary cardiac arrhythmia syndromes has had a remarkable impact on the management of these disorders, especially in patients with the long-QT syndrome. The availability of a genetic diagnostic test has added an important diagnostic tool, providing new opportunities for patient management such as early (presymptomatic) identification and treatment of patients at risk of developing fatal arrhythmias, risk stratification, and installation of gene-specific therapy. However, the fact that the identification of the causal mutation within a family allows diagnosis in other family members independently from the ECG features and arrhythmic manifestations quickly led to the recognition that extensive variability in clinical manifestations (e.g., extent of ECG abnormality and/or symptomatology) may be observed among family members carrying an identical mutation in a single ion channel gene. It is commonly held that this clinical variability stems from interactions between environmental and genetic modifiers with the particular pathogenic mutation. This Molecular Perspectives article reviews current knowledge on these modifiers of disease expression in the cardiac arrhythmia syndromes with particular reference to genetic modifiers.
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Variant 8:Gene:Genomic location:chr3:38620907dbSNP ID:Alias:SCN5A:S1103YTarget disease:Arrhythmia(HP:0011675)Effect type:ExpressivityModifier effect:Risk factorEvidence:From review articleEffect:This genetic variance may contribute as a second genetic modifier for arrhythmia development is under current investigation.Reference:Title:Susceptibility genes and modifiers for cardiac arrhythmias.Species studied:HumanAbstract:The last decade has seen a dramatic increase in the understanding of the molecular basis of arrhythmias. Much of this new information has been driven by genetic studies that focused on rare, monogenic arrhythmia syndromes that were accompanied or followed by cellular electrophysiological or biochemical studies. The marked clinical heterogeneity known from these familial arrhythmia syndromes has led to the development of a multifactorial (multi-hit) concept of arrhythmogenesis in which causal gene mutations have a major effect on disease expression that is further modified by other factors such as age, gender, sympathetic tone, and environmental triggers. Systematic genetic studies have unraveled an unexpected DNA sequence variance in these arrhythmia genes that has ethnic-specific patterns. Whether this genetic variance may contribute as a second genetic modifier for arrhythmia development is under current investigation. The aim of this article is to review common genetic variation in ion channel genes and to compare these recent findings.
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Variant 9:Gene:Genomic location:chr3:38620946dbSNP ID:Target disease:Arrhythmia(HP:0011675)Effect type:ExpressivityModifier effect:Risk factorEvidence:From review articleEffect:This genetic variance may contribute as a second genetic modifier for arrhythmia development is under current investigation.Reference:Title:Susceptibility genes and modifiers for cardiac arrhythmias.Species studied:HumanAbstract:The last decade has seen a dramatic increase in the understanding of the molecular basis of arrhythmias. Much of this new information has been driven by genetic studies that focused on rare, monogenic arrhythmia syndromes that were accompanied or followed by cellular electrophysiological or biochemical studies. The marked clinical heterogeneity known from these familial arrhythmia syndromes has led to the development of a multifactorial (multi-hit) concept of arrhythmogenesis in which causal gene mutations have a major effect on disease expression that is further modified by other factors such as age, gender, sympathetic tone, and environmental triggers. Systematic genetic studies have unraveled an unexpected DNA sequence variance in these arrhythmia genes that has ethnic-specific patterns. Whether this genetic variance may contribute as a second genetic modifier for arrhythmia development is under current investigation. The aim of this article is to review common genetic variation in ion channel genes and to compare these recent findings.
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Variant 10:Gene:Genomic location:Target disease:Brugada Syndrome(DOID_0050451)Effect type:ExpressivityModifier effect:Altered severityEvidence:From review articleEffect:Individuals with the mutation present with a more severe phenotype including spontaneous atrial tachyarrhythmia at young age.Reference:Title:Reduced Penetrance and Variable Expression of SCN5A Mutations and the Importance of Co-inherited Genetic Variants: Case Report and Review of the Literature.Species studied:HumanAbstract:Mutations in the SCN5A gene are responsible for multiple phenotypical presentations including Brugada syndrome, long QT syndrome, progressive familial heart block, sick sinus syndrome, dilated cardiomyopathy, lone atrial fibrillation and multiple overlap syndromes. These different phenotypic expressions of a mutation in a single gene can be explained by variable expression and reduced penetrance. One of the possible explanations of these phenomena is the co-inheritance of genetic variants. We describe a family where the individuals exhibit a compound heterozygosity in the SCN5A gene including a mutation (R1632H) and a new variant (M858L). Individuals with both the mutation and new variant present with a more severe phenotype including spontaneous atrial tachyarrhythmia at young age. We give an overview of the different phenotypes of SCN5A disease and discuss the importance of co-inherited genetic variants in the expression of SCN5A disease.
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Variant 11:Gene:Genomic location:chr3:38645420dbSNP ID:Alias:SCN5A:p.H558R, SCN5A:H558R, SCN5A:rs1805124Target disease:Arrhythmia(HP:0011675)Effect type:ExpressivityModifier effect:Risk factorEvidence:From review articleEffect:This genetic variance may contribute as a second genetic modifier for arrhythmia development is under current investigation.Reference:Title:Susceptibility genes and modifiers for cardiac arrhythmias.Species studied:HumanAbstract:The last decade has seen a dramatic increase in the understanding of the molecular basis of arrhythmias. Much of this new information has been driven by genetic studies that focused on rare, monogenic arrhythmia syndromes that were accompanied or followed by cellular electrophysiological or biochemical studies. The marked clinical heterogeneity known from these familial arrhythmia syndromes has led to the development of a multifactorial (multi-hit) concept of arrhythmogenesis in which causal gene mutations have a major effect on disease expression that is further modified by other factors such as age, gender, sympathetic tone, and environmental triggers. Systematic genetic studies have unraveled an unexpected DNA sequence variance in these arrhythmia genes that has ethnic-specific patterns. Whether this genetic variance may contribute as a second genetic modifier for arrhythmia development is under current investigation. The aim of this article is to review common genetic variation in ion channel genes and to compare these recent findings.
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Variant 12:Gene:Genomic location:chr3:38645420dbSNP ID:Alias:SCN5A:p.H558R, SCN5A:H558R, SCN5A:rs1805124Target disease:Arrhythmia(HP:0011675)Effect type:ExpressivityModifier effect:Altered severityEvidence:From review articleEffect:SCN5A may also account for more severe phenotypic manifestations in conduction disease31 and Brugada syndrome,may exacerbate or alleviate the severity of the disease.Reference:Title:The primary arrhythmia syndromes: same mutation, different manifestations. Are we starting to understand whySpecies studied:HumanAbstract:The discovery of pathogenic mutations primarily in genes encoding cardiac ion-channel proteins underlying the primary cardiac arrhythmia syndromes has had a remarkable impact on the management of these disorders, especially in patients with the long-QT syndrome. The availability of a genetic diagnostic test has added an important diagnostic tool, providing new opportunities for patient management such as early (presymptomatic) identification and treatment of patients at risk of developing fatal arrhythmias, risk stratification, and installation of gene-specific therapy. However, the fact that the identification of the causal mutation within a family allows diagnosis in other family members independently from the ECG features and arrhythmic manifestations quickly led to the recognition that extensive variability in clinical manifestations (e.g., extent of ECG abnormality and/or symptomatology) may be observed among family members carrying an identical mutation in a single ion channel gene. It is commonly held that this clinical variability stems from interactions between environmental and genetic modifiers with the particular pathogenic mutation. This Molecular Perspectives article reviews current knowledge on these modifiers of disease expression in the cardiac arrhythmia syndromes with particular reference to genetic modifiers.
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Variant 13:Gene:Genomic location:chr3:38645420dbSNP ID:Alias:SCN5A:p.H558R, SCN5A:H558R, SCN5A:rs1805124Target disease:Brugada Syndrome(DOID_0050451)Effect type:PenetranceModifier effect:Altered incidenceEvidence:The SCN5A expression level was significantly higher and the methylation rate was significantly lower in sections with H558R (N=10) than those without (0.98±0.14 vs. 0.83±0.19, P=0.04; 0.7±0.2% vs. 1.6±0.1%, P=0.004, respectively).Effect:The H558R may contribute to the protective effects in heterozygous mutations.Reference:Title:H558R, a common SCN5A polymorphism, modifies the clinical phenotype of Brugada syndrome by modulating DNA methylation of SCN5A promoters.Species studied:HumanAbstract:A common SCN5A polymorphism H558R (c.1673 A>G, rs1805124) improves sodium channel activity in mutated channels and known to be a genetic modifier of Brugada syndrome patients (BrS). We investigated clinical manifestations and underlying mechanisms of H558R in BrS.
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Variant 14:Gene:Genomic location:chr3:38645420dbSNP ID:Alias:SCN5A:p.H558R, SCN5A:H558R, SCN5A:rs1805124Target disease:Heart conduction disease(DOID_10273)Effect type:ExpressivityModifier effect:Altered gene activityEvidence:Pedigree analysisEffect:a common SCN5A polymorphism (H558R) in the Na(+) channel I-II interdomain cytoplasmic linker, present in 20% of the population, can mitigate the in vitro effects of a nearby mutation (T512I) on Na(+) channel function.Reference:Title:A common SCN5A polymorphism modulates the biophysical effects of an SCN5A mutationSpecies studied:HumanAbstract:Our understanding of the genetic basis of disease has expanded with the identification of rare DNA sequence variations (mutations) that evoke inherited syndromes such as cystic fibrosis, congenital epilepsy, and cardiac arrhythmias. Common sequence variants (polymorphisms) have also been implicated as risk factors in multiple diseases. Mutations in SCN5A, the cardiac Na(+) channel gene, that cause a reduction in Na(+) current may evoke severe, life-threatening disturbances in cardiac rhythm (i.e., Brugada syndrome), isolated cardiac conduction disease, or combinations of these disorders. Conduction disease is manifest clinically as heart rate slowing (bradycardia), syncope, or lightheadedness. Recent electrophysiologic studies reveal that mutations in particular families exhibiting cardiac conduction disease cause marked effects on several competing voltage-dependent gating processes, but nonetheless cause a mild net reduction in Na(+) current. Here we show that a common SCN5A polymorphism (H558R) in the Na(+) channel I-II interdomain cytoplasmic linker, present in 20% of the population, can mitigate the in vitro effects of a nearby mutation (T512I) on Na(+) channel function. The mutation and the polymorphism were both found in the same allele of a child with isolated conduction disease, suggesting a direct functional association between a polymorphism and a mutation in the same gene.
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Variant 15:Gene:Genomic location:chr3:38645420dbSNP ID:Alias:SCN5A:p.H558R, SCN5A:H558R, SCN5A:rs1805124Target disease:Long QT Syndrome(DOID_2843)Effect type:PenetranceModifier effect:Altered incidenceEvidence:From review articleEffect:Protective effectReference:Title:Identification of a KCNQ1 polymorphism acting as a protective modifier against arrhythmic risk in long-QT syndrome.Species studied:HumanAbstract:Long-QT syndrome (LQTS) is characterized by such striking clinical heterogeneity that, even among family members carrying the same mutation, clinical outcome can range between sudden death and no symptoms. We investigated the role of genetic variants as modifiers of risk for cardiac events in patients with LQTS.
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Variant 16:Gene:Genomic location:chr3:38645420dbSNP ID:Alias:SCN5A:p.H558R, SCN5A:H558R, SCN5A:rs1805124Target disease:Long QT Syndrome(DOID_2843)Effect type:ExpressivityModifier effect:Altered severityEvidence:From review articleEffect:Rescue normal phenotype in LQT3Reference:Title:Modifier genes for sudden cardiac death.Species studied:HumanAbstract:Genetic conditions, even those associated with identical gene mutations, can present with variable clinical manifestations. One widely accepted explanation for this phenomenon is the existence of genetic factors capable of modifying the consequences of disease-causing mutations (modifier genes). Here, we address the concepts and principles by which genetic factors may be involved in modifying risk for cardiac arrhythmia, then discuss the current knowledge and interpretation of their contribution to clinical heterogeneity. We illustrate these concepts in the context of two important clinical conditions associated with risk for sudden cardiac death including a monogenic disorder (congenital long QT syndrome) in which the impact of modifier genes has been established, and a complex trait (life-threatening arrhythmias in acute myocardial infarction) for which the search for genetic modifiers of arrhythmic risk is more challenging. Advances in understanding the contribution of modifier genes to a higher or lower propensity towards sudden death should improve patient-specific risk stratification and be a major step towards precision medicine.
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Variant 17:Gene:Genomic location:chr3:38645558dbSNP ID:Target disease:Arrhythmia(HP:0011675)Effect type:ExpressivityModifier effect:Altered severityEvidence:From review articleEffect:SCN5A may also account for more severe phenotypic manifestations in conduction disease31 and Brugada syndrome,may exacerbate or alleviate the severity of the disease.Reference:Title:The primary arrhythmia syndromes: same mutation, different manifestations. Are we starting to understand whySpecies studied:HumanAbstract:The discovery of pathogenic mutations primarily in genes encoding cardiac ion-channel proteins underlying the primary cardiac arrhythmia syndromes has had a remarkable impact on the management of these disorders, especially in patients with the long-QT syndrome. The availability of a genetic diagnostic test has added an important diagnostic tool, providing new opportunities for patient management such as early (presymptomatic) identification and treatment of patients at risk of developing fatal arrhythmias, risk stratification, and installation of gene-specific therapy. However, the fact that the identification of the causal mutation within a family allows diagnosis in other family members independently from the ECG features and arrhythmic manifestations quickly led to the recognition that extensive variability in clinical manifestations (e.g., extent of ECG abnormality and/or symptomatology) may be observed among family members carrying an identical mutation in a single ion channel gene. It is commonly held that this clinical variability stems from interactions between environmental and genetic modifiers with the particular pathogenic mutation. This Molecular Perspectives article reviews current knowledge on these modifiers of disease expression in the cardiac arrhythmia syndromes with particular reference to genetic modifiers.
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Variant 18:Gene:Genomic location:chr3:38674699dbSNP ID:Target disease:Arrhythmia(HP:0011675)Effect type:ExpressivityModifier effect:Risk factorEvidence:From review articleEffect:This genetic variance may contribute as a second genetic modifier for arrhythmia development is under current investigation.Reference:Title:Susceptibility genes and modifiers for cardiac arrhythmias.Species studied:HumanAbstract:The last decade has seen a dramatic increase in the understanding of the molecular basis of arrhythmias. Much of this new information has been driven by genetic studies that focused on rare, monogenic arrhythmia syndromes that were accompanied or followed by cellular electrophysiological or biochemical studies. The marked clinical heterogeneity known from these familial arrhythmia syndromes has led to the development of a multifactorial (multi-hit) concept of arrhythmogenesis in which causal gene mutations have a major effect on disease expression that is further modified by other factors such as age, gender, sympathetic tone, and environmental triggers. Systematic genetic studies have unraveled an unexpected DNA sequence variance in these arrhythmia genes that has ethnic-specific patterns. Whether this genetic variance may contribute as a second genetic modifier for arrhythmia development is under current investigation. The aim of this article is to review common genetic variation in ion channel genes and to compare these recent findings.