Submissions for variant NM_000335.5(SCN5A):c.4864C>T (p.Arg1622Ter)

dbSNP: rs137854613

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183087	SCV000235497	pathogenic	not provided	2024-04-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation, as the last 394 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Published functional studies demonstrate that R1623X results in no inward sodium current, indicating this variant causes a non-functional sodium channel (PMID: 16325048); This variant is associated with the following publications: (PMID: 19027780, 18436145, 17368591, 30147658, 20539757, 20129283, 28341781, 28552050, 15840483, 26187847, 30203441, 14523039, 31043699, 33221895, 31402444, 32600061, 33087929, 33131149, 28069705, 29574140, 16325048)
Eurofins Ntd Llc (ga)	RCV000183087	SCV000343486	pathogenic	not provided	2016-07-31	criteria provided, single submitter	clinical testing
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000465149	SCV000541078	pathogenic	Familial isolated arrhythmogenic right ventricular dysplasia		criteria provided, single submitter	research
Ambry Genetics	RCV000622049	SCV000737901	pathogenic	Cardiovascular phenotype	2022-06-15	criteria provided, single submitter	clinical testing	The p.R1623* pathogenic mutation (also known as c.4867C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 4867. This changes the amino acid from an arginine to a stop codon within coding exon 27. This alteration was first reported in a pediatric patient with sick sinus syndrome who also carried a second missense alteration in SCN5A. The p.R1623* mutation was also seen in the patient's mother, maternal aunt and maternal grandmother who were all found to have heart block (Benson DW et al. J. Clin. Invest., 2003 Oct;112:1019-28). This alteration has also been reported in subjects with clinical Brugada syndrome (Todd SJ et al. Heart Rhythm, 2005 May;2:540-3; Makiyama T et al. J. Am. Coll. Cardiol., 2005 Dec;46:2100-6) and has been seen in a subject with arrhythmogenic right ventricular cardiomyopathy (ARVC) who also harbored a splicing alteration in PKP2 (Te Riele AS et al. Cardiovasc. Res., 2017 Jan;113:102-111). Functional studies support that this alteration results in a non-functional sodium channel (Benson DW et al. J. Clin. Invest., 2003 Oct;112:1019-28; Makiyama T et al. J. Am. Coll. Cardiol., 2005 Dec;46:2100-6; Gui J et al. PLoS ONE, 2010 Jun;5:e10985). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183087	SCV001219509	pathogenic	not provided	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1623*) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 394 amino acid(s) of the SCN5A protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with bradychardia or Brugada syndrome (PMID: 14523039, 16325048, 29574140). ClinVar contains an entry for this variant (Variation ID: 9374). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects SCN5A function (PMID: 14523039, 16325048, 20539757). This variant disrupts a region of the SCN5A protein in which other variant(s) (p.Arg1629*) have been determined to be pathogenic (PMID: 18361072, 20129283, 25829473). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001841231	SCV001355489	pathogenic	Cardiac arrhythmia	2023-09-14	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 28 of the SCN5A gene, creating a premature translation stop signal in the last exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein with disrupted transmembrane domain DIV (a.a. 1524-1772) and C-terminal region (a.a. 1773-2016). Functional studies have shown that this variant results in the loss of detectable inward sodium current (PMID: 16325048, 20539757). This variant has been reported in at least four unrelated individuals affected with Brugada syndrome (PMID: 15840483, 16325048, 28341781, 33221895) and in another two individuals suspected of having Brugada syndrome (PMID: 20129283). This variant has also been reported in an individual affected with congenital sick sinus syndrome (PMID: 14523039), in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 28069705), and in a pediatric proband affected with sudden cardiac arrest and death (PMID: 26187847). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Multiple truncation variants occurring downstream of this variant are known to be disease-causing (ClinVar variation ID: 1070823, 201573), suggesting that the impacted region is critical for SCN5A protein function. Loss of function is a known mechanism of disease for the SCN5A gene. Based on the available evidence, this variant is classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002496317	SCV002809686	pathogenic	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2021-10-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV004528097	SCV004014721	pathogenic	SCN5A-related disorder	2022-12-15	criteria provided, single submitter	clinical testing	The SCN5A c.4867C>T (p.Arg1623Ter) variant, also referred to as c.4864C>T (p.Arg1622Ter), is a nonsense variant that results in the substitution of arginine at amino acid position 1623 with a stop codon. This variant occurs in the last exon of the gene and may escape nonsense-mediated mRNA decay. The c.4867C>T variant has been reported in a heterozygous state in at least five individuals, including four with Brugada syndrome (BrS) and one individual with left ventricular noncompaction, ventricular tachycardia, and prolonged QT (PMID: 16325048; PMID: 15840483; PMID: 32600061; PMID: 33221895). One of the individuals with BrS was also noted to have a brother who carried the variant and presented with features suggestive of BrS (PMID: 15840483). Two additional individuals have been reported with either confirmed or possible BrS (PMID: 20129283) and the variant has also been reported in a compound heterozygous state in an individual with sick sinus syndrome (PMID: 14523039). Three family members of the individual with sick sinus syndrome who carried the variant were not identified as affected, but were noted to have first-degree heart block (PMID: 14523039). The c.4867C>T variant was not detected in 1410 control individuals (PMID: 14523039; PMID: 20129283) and at least 150 additional control chromosomes. This variant failed filters in the Genome Aggregation Database version 2.1.1 and version 3.1.2; therefore, this information cannot be reliably used. Three patch clamp studies in HEK293 cells overexpressing the c.4867C>T variant demonstrated no Na+ current detection compared to wild type (PMID: 14523039; PMID: 16325048; PMID: 20539757). Similar results of no Na+ current detection were obtained when Xenopus oocytes were injected with variant cRNA when compared to wild type. A cell surface biotinylation experiment using HEK293 cells transfected with the c.4867C>T variant showed very small fractions at the plasma membrane suggesting trafficking deficiency (PMID: 20539757). Based on the available evidence, the c.4867C>T (p.Arg1623Ter) variant is classified as pathogenic for SCN5A-related disorders.
All of Us Research Program, National Institutes of Health	RCV003996083	SCV004843396	pathogenic	Brugada syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 28 of the SCN5A gene, creating a premature translation stop signal in the last exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein with disrupted transmembrane domain DIV (a.a. 1524-1772) and C-terminal region (a.a. 1773-2016). Functional studies have shown that this variant results in the loss of detectable inward sodium current (PMID: 16325048, 20539757). This variant has been reported in at least four unrelated individuals affected with Brugada syndrome (PMID: 15840483, 16325048, 28341781, 33221895) and in another two individuals suspected of having Brugada syndrome (PMID: 20129283). This variant has also been reported in an individual affected with congenital sick sinus syndrome (PMID: 14523039), in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 28069705), and in a pediatric proband affected with sudden cardiac arrest and death (PMID: 26187847). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Multiple truncation variants occurring downstream of this variant are known to be disease-causing (ClinVar variation ID: 1070823, 201573), suggesting that the impacted region is critical for SCN5A protein function. Loss of function is a known mechanism of disease for the SCN5A gene. Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003996083	SCV004848056	pathogenic	Brugada syndrome	2017-05-12	criteria provided, single submitter	clinical testing	The p.Arg1623X variant in SCN5A has been reported in 2 heterozygous individuals with Brugada syndrome (Todd 2005, Mikayama 2005), 1 compound heterozygous individual with sick sinus syndrome (Benson 2003), and one heterozygous individual with ARVC who also carried a heterozygous pathogenic splice variant in PKP2 (te Riele 2017). The p.Arg1623X variant segregated with Brugada syndrome in one family member and with heart block in 3 family members (Benson 2003, Todd 2005). This variant was also absent from large population studies. This variant has also been reported in ClinVar (Variation ID 9374). This nonsense variant leads to a premature termination codon at position 1623. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. While the effect on the protein is unknown, in vitro functional studies provide some evidence that the p.Arg1623X variant causes a loss of function (Benson 2003, Makiyama 2005, Gui 2010). Heterozygous loss of function variants of the SCN5A gene have been previously reported for DCM (Olson 2005), Brugada syndrome (Kapplinger 2010), ventricular fibrillation (Chen 1998), and atrioventricular block and cardiac conduction defects (Baruteau 2012). In summary, this variant meets criteria to be classified as pathogenic for SCN5A-related disorders in an autosomal dominant manner based upon segregation studies, absence from controls, functional evidence, and impact to the protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001841231	SCV005076077	pathogenic	Cardiac arrhythmia	2024-04-29	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.4867C>T (p.Arg1623X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 4.1e-06 in 1461728 control chromosomes (gnomAD v4.1). c.4867C>T has been reported in the literature in multiple individuals affected with cardiac phenotypes including sick sinus syndrome, first-degree heart block, or Brugada syndrome (e.g. Benseon_2003, Ciconte_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 14523039, 33221895). ClinVar contains an entry for this variant (Variation ID: 9374). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000009968	SCV000030189	pathogenic	Sick sinus syndrome 1	2003-10-01	no assertion criteria provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477950	SCV000536699	pathogenic	Long QT syndrome 3	2014-10-31	no assertion criteria provided	research