chr3-38606790-C-T

Position:

chr3-38606790-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1PM2PP2BP4_Moderate

The ENST00000423572.7(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
ENST00000423572.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:9O:1

Conservation

PhyloP100: 0.351

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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, 9 uncertain in ENST00000423572.7

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ 2.7504 (greater than the threshold 3.09). Trascript score misZ 4.8279 (greater than threshold 3.09). GenCC has associacion of gene with progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.18627536).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.1019G>A	p.Arg340Gln	missense_variant	9/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 linkuse as main transcript	c.1019G>A	p.Arg340Gln	missense_variant	9/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.1019G>A	p.Arg340Gln	missense_variant	9/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.1019G>A	p.Arg340Gln	missense_variant	9/28	1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000725

AC:

AN:

248438

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

134716

show subpopulations

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 SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.0000940

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1461166

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

726838

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000125

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000599

Hom.:

Bravo

AF:

0.000128

ExAC

AF:

0.0000909

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:9Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 25, 2023	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) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 05, 2023	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 long-QT syndrome (PMID: 15176425, 21306642, 24144883). 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Cardiac arrhythmia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 13, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 03, 2024	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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 26, 2024

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. The variant allele was found at a frequency of 4.3e-05 in 1613518 control chromosomes, predominantly at a frequency of 0.00031 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 12-fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Cardiomyopathy phenotype (2.5e-05). 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 VUS-possibly benign. -

Brugada syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 09, 2021

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2023

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. -

Congenital long QT syndrome

Other:1

not provided, no classification provided

literature only

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

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

CardioboostCm

Benign

0.0066

BayesDel_addAF

Uncertain

0.012

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

.;.;.;.;.;D;.;.;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.61

.;T;T;T;T;T;T;.;T

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.19

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.020

MutationAssessor

Benign

0.17

.;N;.;.;.;N;.;.;.

MutationTaster

Benign

0.98

N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.34

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

GERP RS

2.8

Varity_R

0.073

gMVP

0.86

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over