rs794728940

Variant names:

• chr3-38550542-G-A
• rs794728940
• NM_001099404.2:c.5830C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Strong PP5

The NM_001099404.2(SCN5A):​c.5830C>T​(p.Arg1944*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000992 in 1,613,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: SCN5A NM_001099404.2 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:8 O:1
• Conservation: PhyloP100: 4.91
• Publications: 4 publications found

Genes affected

SCN5A (HGNC:10593): (sodium voltage-gated channel alpha subunit 5) The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2022]

SCN5A Gene-Disease associations (from GenCC):

• Brugada syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Brugada syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1E

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• sick sinus syndrome 1

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial heart block, type 1A

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• atrial standstill

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sick sinus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal familial ventricular fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PP5: Variant 3-38550542-G-A is Pathogenic according to our data. Variant chr3-38550542-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 201596.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.5830C>T	p.Arg1944*	stop_gained	Exon 28 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.5827C>T	p.Arg1943*	stop_gained	Exon 28 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.5830C>T	p.Arg1944*	stop_gained	Exon 28 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.5827C>T	p.Arg1943*	stop_gained	Exon 28 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248022 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461058 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726716

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.0000672 AC: 3 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111418

Other (OTH) AF: 0.0000994 AC: 6 AN: 60342

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74386

African (AFR) AF: 0.00 AC: 0 AN: 41476

American (AMR) AF: 0.000262 AC: 4 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000211 Hom.: 0

Bravo AF: 0.0000907

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:3

Nov 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Sep 17, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 26, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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) -

Nov 15, 2022

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

SCN5A-related disorder Pathogenic:2 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: 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. -

-

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Cardiovascular phenotype Uncertain:2

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_mod;PM2 -

Feb 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Congenital long QT syndrome Pathogenic:1

-

Genetics and Genomics Program, Sidra Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: 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). -

not specified Uncertain:1

Oct 12, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Brugada syndrome Uncertain:1

Aug 27, 2024

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiac arrhythmia Uncertain:1

May 21, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		4.9
Vest4		0.87
GERP RS		4.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs794728940; hg19: chr3-38592033; COSMIC: COSV61142776; COSMIC: COSV61142776;