3-38606790-C-T

Variant names:

• chr3-38606790-C-T
• rs191009474
• NM_001099404.2:c.1019G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_001099404.2(SCN5A):​c.1019G>A​(p.Arg340Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,613,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R340W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:11 O:1
• Conservation: PhyloP100: 0.351
• Publications: 9 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 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001099404.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.18627536).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.1019G>A	p.Arg340Gln	missense_variant	Exon 9 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.1019G>A	p.Arg340Gln	missense_variant	Exon 9 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.1019G>A	p.Arg340Gln	missense_variant	Exon 9 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.1019G>A	p.Arg340Gln	missense_variant	Exon 9 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000725 AC: 18 AN: 248438 AF XY: 0.000104

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0000940

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000342 AC: 50 AN: 1461166 Hom.: 0 Cov.: 31 AF XY: 0.0000371 AC XY: 27 AN XY: 726838

African (AFR) AF: 0.000239 AC: 8 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86212

European-Finnish (FIN) AF: 0.000113 AC: 6 AN: 53166

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111672

Other (OTH) AF: 0.0000331 AC: 2 AN: 60350

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74508

African (AFR) AF: 0.000361 AC: 15 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15304

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.000128

ExAC AF: 0.0000909 AC: 11

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:11 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:3

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 25, 2023

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with Long QT syndrome and in at least one individual with early-onset lone atrial fibrillation. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 22685113) -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 340 of the SCN5A protein (p.Arg340Gln). This variant is present in population databases (rs191009474, gnomAD 0.03%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 15176425, 21306642, 24144883, 25175087). ClinVar contains an entry for this variant (Variation ID: 67626). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects SCN5A function (PMID: 22685113). 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. -

Brugada syndrome 1 Uncertain:2

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2025

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria used: PM1, PS4_Supporting, PM2_supporting. -

Cardiovascular phenotype Uncertain:2

May 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R340Q variant (also known as c.1019G>A), located in coding exon 8 of the SCN5A gene, results from a G to A substitution at nucleotide position 1019. The arginine at codon 340 is replaced by glutamine, an amino acid with highly similar properties, and is located in the DI-S5/S6 transmembrane-spanning region. This variant has been detected in a dilated cardiomyopathy case, long QT syndrome cohort, sudden death cohorts, and in lone atrial fibrillation cohorts; however details were limited in and additional variants were detected in some cases (Fodstad H et al. Ann. Med., 2004;36 Suppl 1:53-63; Winkel BG et al. BMC Med. Genet., 2011 Feb;12:22; Olesen MS et al. Circ Cardiovasc Genet, 2012 Aug;5:450-9; Christiansen SL et al. Eur. J. Hum. Genet., 2016 12;24:1797-1802; Lin Y et al. Circ Cardiovasc Genet, 2017 Dec;10; Delio M et al. PLoS One, 2015 Jul;10:e0133742). One study indicated this variant may have some impact to channel function (Olesen MS et al. Circ Cardiovasc Genet, 2012 Aug;5:450-9). This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

- -

Cardiac arrhythmia Uncertain:2

Jan 03, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 340 of the SCN5A protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. A functional study has shown that this variant causes a negative voltage shift of both steady-state activation and inactivation, together with a reduced time constant in transfected HEK293 cells (PMID: 22685113). This variant has been reported in an individual affected with long-QT syndrome (PMID: 15176425), in an individual affected with lone atrial fibrillation (PMID: 21306642), and in an individual affected with sudden unexplained death (PMID: 24631775). This variant has been identified in 21/279838 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. -

Aug 13, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 340 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant causes a negative voltage shift of both steady-state activation and inactivation, together with a reduced time constant in transfected HEK293 cells (PMID: 22685113). This variant has been reported in an individual affected with long-QT syndrome (PMID: 15176425), in an individual affected with lone atrial fibrillation (PMID: 21306642), and in an individual affected with sudden unexplained death (PMID: 24631775). This variant has been identified in 21/279838 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. -

not specified Uncertain:1

Jan 27, 2025

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.1019G>A (p.Arg340Gln) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. This frequency is not significantly higher than estimated for a pathogenic variant in SCN5A causing Brugada Syndrome (4.3e-05 vs 0.00017), allowing no conclusion about variant significance. c.1019G>A has been reported in the literature in the heterozygous state in multiple individuals affected with SCN5A-related conditions, including atrial fibrillation, long QT syndrome, dilated cardiomyopathy, and sudden unexplained death (example, Christiansen_2016, Delio_2015, Fodstad_2004, Lin_2017, Oleson_2012, Oleson_2014, Winkel_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. One publication reported in vitro experimental evidence evaluating an impact on protein function using HEK293 cells, however, does not allow convincing conclusions about the variant effect (example, Oleson_2012). The following publications have been ascertained in the context of this evaluation (PMID: 27650965, 26214305,15176425, 29247119, 22685113, 24144883, 21306642). ClinVar contains an entry for this variant (Variation ID: 67626). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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 Uncertain:1

Sep 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital long QT syndrome Other:1

-

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15176425;PMID:19862833;PMID:22685113). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
CardioboostArm	Benign	0.00041
CardioboostCm	Benign	0.0066
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	21
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	.;.;.;.;.;D;.;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.61	.;T;T;T;T;T;T;.;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.020	T
MutationAssessor	Benign	0.17	.;N;.;.;.;N;.;.;.
PhyloP100		0.35
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.21	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.56	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.38	T;T;T;T;T;T;T;T;T
Polyphen		0.85	P;D;.;P;.;D;D;.;.
Vest4		0.76
MVP		0.92
MPC		0.41
ClinPred		0.015	T
GERP RS		2.8
Varity_R		0.073
gMVP		0.86
Mutation Taster		=1/99	disease causing

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: rs191009474; hg19: chr3-38648281; COSMIC: COSV61125222;