rs794728940

chr3-38550542-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001099404.2(SCN5A):c.5830C>T(p.Arg1944Ter) 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:5 O:1
• Conservation: PhyloP100: 4.91

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 201596.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Likely_pathogenic=4, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.5830C>T	p.Arg1944Ter	stop_gained	28/28	ENST00000413689.6
SCN5A	NM_000335.5	c.5827C>T	p.Arg1943Ter	stop_gained	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.5830C>T	p.Arg1944Ter	stop_gained	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.5827C>T	p.Arg1943Ter	stop_gained	28/28	1	NM_000335.5	A1

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

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248022 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134634

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000994

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 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:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Sep 17, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2022	Identified in the literature in an infant with sudden unexplained (Wang et al., 2014) and in an individual with Brugada syndrome (Ciconte et al., 2021); however, both patients also harbored an additional variant in the SCN5A gene and no segregation data was reported; Identified by clinical exome sequencing in a patient with skeletal muscle involvement but no evidence of cardiac involvement in the literature (Monies et al., 2019); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 73 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29247119, 28316956, 28370132, 31698696, 33221895, 24631775, 31130284) -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 15, 2022	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

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 12, 2023

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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2024

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. -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 22, 2023

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
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
Vest4		0.87
GERP RS		4.0

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

Publications

LitVar

Other links and lift over

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