Submissions for variant NM_000335.5(SCN5A):c.5827C>T (p.Arg1943Ter)

gnomAD frequency: 0.00004  dbSNP: rs794728940

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183202	SCV000235621	uncertain significance	not provided	2024-11-26	criteria provided, single submitter	clinical testing	Identified in the literature in an infant with sudden unexplained death and in an individual with Brugada syndrome; however, both patients also harbored an additional variant in the SCN5A gene and no segregation data was reported (PMID: 24631775, 33221895); Identified by clinical exome sequencing in a patient with skeletal muscle involvement but no evidence of cardiac involvement in the literature (PMID: 31130284); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation as the last 73 amino acids are lost; This variant is associated with the following publications: (PMID: 29247119, 28316956, 28370132, 31698696, 33221895, 36007526, 24631775, 31130284, 36129056)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183202	SCV000952718	uncertain significance	not provided	2024-11-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1944*) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 73 amino acid(s) of the SCN5A protein. This variant is present in population databases (rs794728940, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with Brugada syndrome and/or sudden unexplained death (PMID: 24631775, 29247119, 33221895, 36007526). ClinVar contains an entry for this variant (Variation ID: 201596). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the SCN5A protein in which other variant(s) (p.Arg2012) have been observed in individuals with SCN5A-related conditions (PMID: 27287068). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001842941	SCV001349233	uncertain significance	Cardiac arrhythmia	2023-03-22	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. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing a disrupted C-terminal region. The C-terminal region has been reported to be critical to sodium channel function (PMID: 16686678, 16798729). However, an experimental functional study has shown that this variant has negligible effects on the protein expression and function (PMID: 28370132). This variant has been reported in an individual affected with Brugada syndrome, who also carried another pathogenic variant in the same gene that could explain the observed phenotype (PMID: 33221895). This variant has also been reported in several young individuals affected with sudden unexplained death (PMID 24631775, 28370132, 29247119) or suspected of having a genetic disorder (PMID: 36007526, 36129056). This variant has been identified in 4/279424 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SCN5A function is a known mechanism of disease (clinicalgenome.org). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
AiLife Diagnostics, AiLife Diagnostics	RCV000183202	SCV002502737	likely pathogenic	not provided	2021-09-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002354485	SCV002648323	uncertain significance	Cardiovascular phenotype	2024-01-02	criteria provided, single submitter	clinical testing	The p.R1944* variant (also known as c.5830C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 5830. This changes the amino acid from an arginine to a stop codon within coding exon 27. This alteration occurs at the 3' terminus of theSCN5A gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 3% of the protein. The exact functional effect of this alteration is unknown. This alteration has been previously reported in a sudden death case, but the infant victim was also heterozygous for a second alteration in SCN5A (p.Q1832E) (Wang D et al. Forensic Sci. Int. 2014;237:90-9). Functional studies indicate that this alteration does not have a significant effect on current density, gating kinetics, or trafficking (Gando I et al. Pacing Clin Electrophysiol. 2017;40:703-712). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV000183202	SCV003802865	uncertain significance	not provided	2022-11-15	criteria provided, single submitter	clinical testing	The SCN5A c.5830C>T (p.Arg1944Ter) nonsense variant results in the substitution of arginine at amino acid position 1944 with a stop codon. This variant occurs in the last exon of the gene and may escape nonsense-mediated mRNA decay. This variant has been reported in a heterozygous state in at least three individuals in the literature, including a proband with Brugada syndrome (PMID: 33221895), and two female infants with sudden infant death syndrome, one of whom carried a second missense variant in SCN5A (PMID: 28370132; PMID: 29247119; PMID: 24631775). This variant is reported in the Genome Aggregation Database in four alleles at a frequency of 0.000262 in the Latino/Admixed American population (version 3.1.2). This frequency is high but may be consistent with reduced penetrance. Patch clamp studies in HEK293 cells overexpressing the Arg1944Ter mutant protein demonstrated no significant alteration in Na(v)1.5 channel kinetics compared to the wild type protein (PMID: 28370132). Based on the available evidence, the c.5830C>T (p.Arg1944Ter) variant is classified as a variant of uncertain significance for SCN5A-related disorders.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000844965	SCV004046047	likely pathogenic	SCN5A-related disorder		criteria provided, single submitter	clinical testing	This nonsense variant is found in the last exon of SCN5A and is predicted to cause loss of normal protein function by protein truncation with loss of the last 73 amino acids of the protein. Another nonsense variant located downstream of this variant has been reported in individuals with SCN5A-related disorders (PMID: 23538271, 28600387, 31447099, 27532257, 19862833). Loss of function variation in SCN5A is an established mechanism of disease (PMID: 14523039, 35305865, 20301690). This variant has been previously reported as a heterozygous change in individuals with cardiac arrhythmia and sudden unexplained death (PMID: 24631775, 28370132, 29247119). However, the individual with sudden unexplained death was reported to have an additional variant in the SCN5A gene and segregation data was not available (PMID: 24631775).The c.5830C>T (p.Arg1944Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (4/279424) and thus is presumed to be rare. Based on the available evidence, the c.5830C>T (p.Arg1944Ter) variant is classified as Likely Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000844965	SCV004046137	likely pathogenic	SCN5A-related disorder		criteria provided, single submitter	clinical testing	This nonsense variant is found in the last exon of SCN5A and is predicted to cause loss of normal protein function by protein truncation with loss of the last 73 amino acids of the protein. This variant has been previously reported as a heterozygous change in patients with cardiac arrhythmia (PMID: 29247119) and sudden unexplained death (SUD) (PMID: 24631775). However, the patient with SUD harbored an additional variant in the SCN5A gene, and segregation data was not available (PMID: 24631775). One other nonsense variant located downstream of this variant has been reported as disease-causing in the literature (PMID: 23538271, 28600387, 31447099, 27532257, 19862833), and loss of function is a known mechanism of disease in the SCN5A gene. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (4/279424) and thus is presumed to be rare. Based on the available evidence, the c.5830C>T (p.Arg1944Ter) variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398912	SCV004122838	uncertain significance	not specified	2023-10-12	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.5830C>T (p.Arg1944X), located within the last exon, results in a premature termination codon and is predicted to cause a truncation of the encoded protein but is not expected to undergo nonsense mediated decay. The variant allele was found at a frequency of 1.2e-05 in 248022 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5830C>T has been reported in the literature in a case of sudden unexplained death in an infant (Wang_2017, Lin_2017), and in an individual with Brugada syndrome, who also harbored a second putatively pathogenic variant in SCN5A (Ciconte_2021). The variant has also been reported in several individuals who underwent genetic testing, but whether they presented with a cardiac phenotype was not specified (e.g. Baruteau_2018, Yang_2022). These reports do not provide unequivocal conclusions about association of the variant with SCN5A-related cardiac conditions. At least one publication reported experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (Gando_2017). The following publications have been ascertained in the context of this evaluation (PMID: 30059973, 33221895, 28370132, 29247119, 24631775, 36129056). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Five classified the variant as uncertain significance and two classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
GenomeConnect, ClinGen	RCV000844965	SCV000986790	not provided	SCN5A-related disorder		no assertion provided	phenotyping only	Variant interpretted as Likely pathogenic and reported on 03/29/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Genetics and Genomics Program, Sidra Medicine	RCV004732756	SCV005367932	likely pathogenic	Congenital long QT syndrome		no assertion criteria provided	research	The c.5830C>T stop gained variant in SCN5A is absent in homozygous form in gnomAD, with a frequency of 0.0000318, indicating rarity (PM2). The variant results in a premature stop codon, likely leading to loss of function (PVS1). It was inherited from the affected mother, supporting its clinical relevance. Based on this evidence, the variant is classified as likely pathogenic (ACMG codes: PVS1, PM2, PP5).
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV004771804	SCV005382566	uncertain significance	Brugada syndrome	2024-08-27	no assertion criteria provided	clinical testing