SCN5A

Inheritance Pattern: SD

Disease ID:MONDO:0007240

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0100234

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0007240

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0016587

Submitter: ClinGen

There is limited evidence that SCN5A is associated with ARVC. Screening of ARVC patient cohorts for SCN5A mutations has been performed in four studies (2589161, 24388542, 18375968, 28069705). The first study (2589161) reported the investigation on 6 young patients who were electrically resuscitated after ventricular fibrillation. One of these patients died suddenly during a four years follow-up and autopsy revealed fibrofatty changes in the right ventricle, a decrease number of myocardial cells as typical features of ARVC. Genetic screening revealed a variant on SCN5A, however no further information about genomic localization and classification of the variant was present. The second study (24388542) reported the case of a 50 year old female patient presenting an enlarged right ventricle with structural myocardial changes. Right ventricular angiography showed sacculations in the so-called triangle of dysplasia resembling ARVC structural changes. Genetic testing identified a loss-of-function variant on SCN5A, however no further information about genomic localization and classification of the variant was present. The third study (18375968) reported the case of 58 years old man presenting monomorphic and polymorphic non-sustained ventricular tachycardias, chest pain and dyspnea at rest, complete RBBB, mild dilatation and hypokinesia of the right ventricular and bioptic investigation revealed cardiac hypertrophy and fibrosis, but no myocardial tissue degeneration. Genetic screening identified a splice error on intron 21 of SCN5A gene c.3840+1 G>A, which results in a loss of function of the sodium channel. However, no segregation data were available and patient’s phenotype does not fulfil a definite ARVC diagnosis. The most recent study (28069705) investigated the entire exome for pathogenic variants among a ‘discovery cohort’ of six unrelated Caucasian patients with a clinical diagnosis of ARVC. Genetic screening identified a heterozygous SCN5A missense variant in a female patient causing the aminoacid substitution Arg1898His. Subsequently, authors analysed a ‘validation cohort’ of 281 unrelated patients for SCN5A variants. Authors identified 5 different variants in 5 patients; among these a missense variant causing the aminoacid substitution Ser1787Asn was excluded due its high frequency in the general population. Two patients were digenic variants carriers, both presenting a different pathogenic variant on PKP2 and an additional variant on SCN5A. Another patient carried a heterozygous in frame deletion (Leu729del), however cascade genetic screening revealed that family members carrying this variants did not fulfill definite ARVC criteria. Finally genetic screening identified a missense variant Tyr416Cys in a 55 years old female but segregation study in the family don’t demonstrate the link of this variant with the clinical phenotype. Experimental data from this last study (28069705) analyzed the role of SCN5A Arg1898His variant. Authors generated an induced pluripotent stem cell-derived cardiomyocytes and then corrected them by using CRISP/Cas9 technology. Whole-cell patch clamping revealed a 36% reduction in peak sodium current and super-resolution and fluorescence microscopy showed reduced abundance of both SCN5A and CDH2 clusters at the intercalated disc. However, experimental data do not showed the link of electrical abnormalities to structural changes typical of ARVC alterations such as myocardial fibrotic replacement. In summary, there is limited evidence to support gene-disease association. There is no clear evidence that the identified SCN5A variants contribute to the ARVC phenotype and there is no known disease mechanism that would link SCN5A with ARVC.

Inheritance Pattern: AD

Disease ID:MONDO:0012061

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0011001

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0019490

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0018054

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:1010181

Submitter: ClinGen

Variants in *SCN5A* have been widely reported in a collection of cardiac rhythm phenotypes with heterogenous expression including autosomal dominant long QT syndrome in 1995 (Wang *et al.* PMID: 7889574), Brugada syndrome in 1998 (Chen *et al.* PMID: 9521325), progressive familial heart block in 1999 (Schott *et al.* PMID: 10471492), and sick sinus syndrome in 2003 (Benson *et al.* PMID: 14523039). The molecular mechanism of disease is reported to be sodium channel dysfunction caused by either loss of function, gain of function, or both (PMIDs: 18451998, 30364184). Individuals with disease-causing variants in *SCN5A* are commonly reported with at least one cardiac rhythm phenotype that includes, but is not limited to, atrial fibrillation, sick sinus syndrome, progressive cardiac conduction disease, ventricular fibrillation, long QT syndrome, and Brugada syndrome. Individuals with pathogenic variants in *SCN5A* may also exhibit overlapping or mixed cardiac rhythm phenotypes and intrafamilial variability (PMID: 34245912). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no significant difference in inheritance pattern and found considerable interfamilial and intrafamilial variability of cardiac rhythm phenotypes. Therefore, the following disease entities have been lumped into one disease entity, termed *SCN5A*-related cardiac rhythm disorder (MONDO:1010181); atrial conduction disease (MONDO:0014500), atrioventricular block (MONDO:0000465), Brugada syndrome (MONDO:0015263), familial atrial fibrillation (MONDO:0018054), familial sick sinus syndrome (MONDO:0012061), long QT syndrome 3 (MONDO:0011377), progressive familial heart block (MONDO:0019490), and ventricular fibrillation, paroxysmal familial, type 1 (MONDO:0011376). In addition, the split curations for *SCN5A* in relation to autosomal dominant dilated cardiomyopathy, autosomal dominant arrhythmogenic right ventricular cardiomyopathy, and autosomal dominant congenital heart disease have been curated separately by other ClinGen gene curation expert panels. Evidence supporting this gene-disease relationship includes case-level data, case-control data, segregation data, and experimental data. Seventeen variants (thirteen missense, one in-frame insertion, two nonsense, one frameshift) that have been reported in seventeen probands in six publications (PMIDs: 10590249, 12051963, 18451998, 27566755, 27810048, 39134129) are included in this curation. Of note, missense variant *SCN5A*:p.E1784K (also known as E1783K) is reported as the most common variant among Brugada syndrome and long QT syndrome patients (PMIDs: 18451998, 27381756). Variants in this gene have also been shown to segregate with disease in family members. One such variant, *SCN5A* 1798insD, alternatively known as NM_000335.5:c.5382_5384dup (p.Tyr1794_Glu1795insAsp), has been extensively reported in a large Dutch pedigree with over 200 members of which carriers displayed clinical signs of long QT syndrome, sinus bradycardia on EEG, progressive cardiac conduction disease, nocturnal sudden death, or Brugada syndrome (PMID: 10590249). This gene-disease relationship has been studied in at least one case-control study at the single variant level, with p value = <0.0001 and confidence interval = 28-200, (p.Gln1118Ter Italian founder variant in relation to Type 1 BrS, CCD, Type 1 BrS pattern or CCD; PMID: 34245912). This gene-disease relationship is supported by animal and cell models, expression and rescue studies. Expression data from adult and embryonic mice heart tissue showed *SCN5A* mRNA expression to be highly specific to the heart (PMID: 19255801). Transgenic mice recapitulate the clinical phenotype observed in human patients, while iPSC-derived cardiomyocyte cell models carrying *SCN5A* variants showed recapitulation of Na+ channel mutation dysfunction (PMIDs: 10590249, 22647976, 27810048). *In vivo* rescue of a transgenic mouse model using genomic base editing by dual-adeno-associated virus-delivered ABE showed alleviation of the long QT phenotype in homozygous and heterozygous *Scn5A* T1307M mice (PMID: 37965733). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. In summary, there is definitive evidence to support the relationship between *SCN5A* and *SCN5A*-related cardiac rhythm disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Hereditary Cardiovascular Disease GCEP and Sodium and Calcium Channel Arrhythmia VCEP on October 8, 2025 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*SCN5A* was first reported in relation to autosomal dominant congenital heart disease in 2017 (Jin et al., PMID: 28991257). Of note, variants in *SCN5A* are associated with a number of arrhythmia phenotypes including Brugada syndrome, dilated cardiomyopathy, and Long QT syndrome, all of which has previously been classified as Definitive. Additionally, *SCN5A* has been classified as Limited for arrhythmogenic right ventricular cardiomyopathy and Disputed for catecholaminergic polymorphic ventricular tachycardia and short QT syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanisms, inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into separate entities: congenital heart disease, dilated cardiomyopathy, familial long QT syndrome, Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome. This curation addresses *SCN5A* in relation to AD congenital heart disease. Two unique missense variants have been reported in two probands in three publications (PMIDs: 28991257, 32368696, 35885997). However, both of the variants had a high minor allele frequency (>0.00001) in gnomAD v4. Both probands were also reported with several variants in other genes, therefore none of the probands were scored. The gene-disease relationship is supported by high expression specifically in the human fetal heart tissue (NCBI fetal expression data, PMID: 26076956). In summary, the evidence supporting the relationship between *SCN5A* and autosomal dominant congenital heart diseases has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *SCN5A* plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date December 9th, 2024 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0011003

Submitter: ClinGen

SCN5A was originally evaluated for DCM by ClinGen DCM GCEP on October 9, 2020. Evidence of the association of this gene with DCM was re-evaluated on 2/21/2025. As a result, the classification did not change. A summary of the information contributing to the classification of the gene at the time of re-evaluation is summarized herein. SCN5A was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2005 (Olson et al., 2005, PMID: 15671429). Human genetic evidence supporting this gene-disease relationship includes case-level data and segregation data. Numerous variants (missense, frameshift, nonsense) have been reported in humans with isolated DCM (Olson et al., 2005, PMID: 15671429; Ge et al., 2008, PMID: 19808398; McNair et al., 2011, PMID: 21596231; Morales et al., 2011, PMID: 20458009; Grosselin-Badaroudine et al., 2012, PMID: 22675453; Laurent et al., 2012, PMID: 22766342; Mann et al., 2012, PMID: 22999724; Zakrzewska-Koperska et al., 2018, PMID: 29871609; Calloe et al., 2018, PMID: 29506689; Gigli et al., 2019, PMID: 31514951; Doisne et al., 2020, PMID: 31930659). This gene-disease association is supported by mouse models, a human iPS cell culture model, and expression studies. SCN5A mRNA levels were markedly decreased in heart tissues obtained from DCM patients (Kepenek et al., 2019, PMID: 31520233). The myosin heavy chain-Snail transgenic mice displayed a DCM phenotype with conduction block and marked reduction of SCN5A expression (Hesse, et al., 2007, PMID: 17512504). Heterozygous and homozygous knock-in mouse models harboring SCN5A p.D1275N found in a patient with DCM displayed a DCM phenotype including intraventricular conduction block with marked reduction of cardiac sodium currents (Watanabe et al., 2011, PMID: 21824921). Furthermore, patient-derived human iPS cell-induced cardiomyocytes carrying SCN5A p.R219H showed reduced contraction, prolonged action potential duration, early afterdepolarization, and H+-leak currents (Moreau et al., 2018, PMID: 30218094). SCN5A has also been curated by the Long QT Syndrome gene curation expert group for familial long qt syndrome (Definitive, 09/25/2018), the Brugada Syndrome gene curation expert group for Brugada syndrome (Definitive, 11/21/2017), the Arrhythmogenic Right Ventricular Cardiomyopathy gene curation expert group for ARVC (Limited, 06/06/2019), the Catecholaminergic Polymorphic Ventricular Tachycardia gene curation expert group for CPVT (Disputed, 01/20/2021), the Short QT Syndrome gene curation expert group for short QT syndrome (Disputed, 10/27/2020), and the Congenital Heart Disease gene curation expert group for congenital heart disease (12/09/2024). In summary, SCN5A is definitively associated with autosomal dominant DCM. This has been repeatedly demonstrated in both the research and clinical diagnostic setting, and has been upheld over time. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on October 9, 2020 (SOP Version 7). This written summary was updated on 02/21/2025 and approved by the DCM GCEP on 05/30/2025.

Inheritance Pattern: AD

Disease ID:MONDO:0011001

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AD

Disease ID:MONDO:0011003

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0016587

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0024562

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0024562

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0011003

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0011001

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0011003

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0011377

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0011377

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0015470

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0011001

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0015281

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0011001

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0011377

Submitter: G2P