rs757532106

Variant names:

• chr3-38550500-G-A
• rs757532106
• NM_001099404.2:c.5872C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-38550500-G-A
• chr3-38550500-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Moderate PP5

The NM_001099404.2(SCN5A):​c.5872C>T​(p.Arg1958*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,608,582 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 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: SCN5A NM_001099404.2 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:5
• Conservation: PhyloP100: 3.08
• Publications: 8 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 3 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. Fraction of 0.0296 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PP5: Variant 3-38550500-G-A is Pathogenic according to our data. Variant chr3-38550500-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 201546.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.5872C>T	p.Arg1958*	stop_gained	Exon 28 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.5869C>T	p.Arg1957*	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.5872C>T	p.Arg1958*	stop_gained	Exon 28 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.5869C>T	p.Arg1957*	stop_gained	Exon 28 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000449 AC: 11 AN: 245204 AF XY: 0.0000451

Gnomad AFR exome AF: 0.0000652

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000941

Gnomad NFE exome AF: 0.00000901

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000316 AC: 46 AN: 1456370 Hom.: 0 Cov.: 31 AF XY: 0.0000415 AC XY: 30 AN XY: 723480

African (AFR) AF: 0.0000898 AC: 3 AN: 33400

American (AMR) AF: 0.000112 AC: 5 AN: 44468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25860

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85756

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.0000199 AC: 22 AN: 1108258

Other (OTH) AF: 0.0000333 AC: 2 AN: 60088

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74364

African (AFR) AF: 0.0000482 AC: 2 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000482 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000661 AC: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:3

Feb 02, 2025

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.Arg1958*) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 59 amino acid(s) of the SCN5A protein. This variant is present in population databases (rs757532106, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of long QT syndrome, dilated cardiomyopathy or unexplained cardiac arrest (PMID: 15840476, 19862833, 24388587, 27532257, 28600387, 29961767, 37652022). This variant is also known as c.5869C>T (p.Arg1957*) . ClinVar contains an entry for this variant (Variation ID: 201546). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal does not substantially affect SCN5A function (PMID: 32533946). This variant disrupts a region of the SCN5A protein in which other variant(s) (p.Arg2012His) 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. -

Jun 21, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 12, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with LQTS, borderline QTc intervals, idopathic arrhythmia, and DCM (Trolle et al., 2013; Chang et al., 2014; Walsh et al., 2017; Mellor et al., 2017); Nonsense variant predicted to result in protein truncation as the last 59 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 15840476, 27532257, 24388587, 19862833, 28600387, 33087929, 32533946, 31447099, 23936059) -

SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

Mar 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1958* variant (also known as c.5872C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 5872. This changes the amino acid from an arginine to a stop codon within coding exon 27. This alteration has been reported in a long QT syndrome cohort, a dilated cardiomyopathy cohort, a Turner syndrome cohort, a hearing loss cohort, and a cardiac arrest survivor cohort (Hedley PL et al. Hum. Mutat. 2009;30:1486-511; Trolle C et al. PLoS ONE. 2013;8:e69614; Chang RK et al. J. Pediatr. 2014;164:590-5.e1-3; Mellor G et al. Circ Cardiovasc Genet. 2017;10:e001686; Walsh R et al. Genet. Med. 2017;19:192-203). This alteration has also been reported in biobank cohorts (Zouk et al. Am J Hum Genet, 2019 Sep;105:588-605; Van Hout CV et al. Nature, 2020 Oct;586:749-756). Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of SCN5A, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 59 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia Uncertain:1

Feb 22, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.5872C>T (p.Arg1958*) variant changes 1 nucleotide in exon 28 of the SCN5A gene, creating a premature translation stop signal. This variant is also described as c.5869C>T (p.Arg1957*) based on a different transcript NM_000335.5. This variant occurs in the last exon and is expected to result in a truncated protein product missing the last 59 amino acids of the protein. To our knowledge, functional studies have not been reported for this variant. However, a different truncation variant p.Arg1944* missing the last 73 amino acids of the protein has shown negligible effects on protein expression and function (PMID: 28370132) (ClinVar variation ID: 201596). This c.5872C>T (p.Arg1958*) variant has been reported in an individual affected with long QT syndrome (PMID: 19862833), in two individuals having borderline long QTc intervals (PMID: 23936059, 24388587), in two individuals with dilated cardiomyopathy (PMID: 27532257, 29961767) and in an individual with unexplained cardiac arrest (PMID: 28600387). This variant has also been identified in 13/276598 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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	0.20	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Benign	0.13
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.37	N
PhyloP100		3.1
Vest4		0.85
GERP RS		4.1
Mutation Taster		=1/199	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: rs757532106; hg19: chr3-38591991;