rs199473145

Positions:

chr3-38597925-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001099404.2(SCN5A):c.2066G>A(p.Arg689His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12O:1

Conservation

PhyloP100: 0.183

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 1 ACMG points.

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 4.7729 (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=0.10350397).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.2066G>A	p.Arg689His	missense_variant	14/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 linkuse as main transcript	c.2066G>A	p.Arg689His	missense_variant	14/28	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.2066G>A	p.Arg689His	missense_variant	14/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.2066G>A	p.Arg689His	missense_variant	14/28	1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000924

AC:

AN:

248792

Hom.:

AF XY:

0.0000815

AC XY:

AN XY:

134928

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.000360

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000355

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000561

AC:

AN:

1461432

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

726964

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.000383

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000133

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3Other:1

not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:15851227;PMID:16414944;PMID:19841300;PMID:21321465;PMID:20129283;PMID:22378279). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2024	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15851227, 19841300, 21321465, 28988457, 29728395, 31043699, 31315195, 24055113, 23465283, 22378279, 25637381, 15996170, 16453024, 26746457, 28341781, 20129283, 27871843, 23692053, 22490985, 34219138, 33232181, 33131149, 35932045, 16414944, 30847666) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 689 of the SCN5A protein (p.Arg689His). This variant is present in population databases (rs199473145, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 15996170, 16453024, 21321465, 23692053, 28341781, 33131149, 33232181). ClinVar contains an entry for this variant (Variation ID: 67710). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 22490985, 23692053, 34219138). 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, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 01, 2022	- -

Long QT syndrome

Uncertain:2

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Apr 05, 2018	- -

Cardiac arrhythmia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces arginine with histidine at codon 689 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). Experimental functional studies have provided contradicting results regarding the impact of this variant on the sodium channel function. One study has suggested that the mutant protein carrying this variant is unable to generate current in transfected cells (PMID: 22490985), while a different study has suggested that most of the channel properties of the mutant protein were similar to the wild type protein (PMID: 23692053). This variant has been reported in individuals affected with Brugada syndrome (PMID: 21321465, 28341781), Brugada-like phenotype (PMID: 22490985), arrhythmia (PMID: 15996170, 23692053), sudden infant death syndrome (PMID: 16453024), and sudden cardiac death (PMID: 23692053). This variant has also been identified in 23/248792 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	Dec 02, 2023	This missense variant replaces arginine with histidine at codon 689 of the SCN5A protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Experimental functional studies have provided contradicting results regarding the impact of this variant on the sodium channel function. One study has suggested that the mutant protein carrying this variant is unable to generate current in transfected cells (PMID: 22490985), while a different study has suggested that most of the channel properties of the mutant protein were similar to the wild type protein (PMID: 23692053). This variant has been reported in individuals affected with Brugada syndrome (PMID: 21321465, 28341781), Brugada-like phenotype (PMID: 22490985), arrhythmia (PMID: 15996170, 23692053), sudden infant death syndrome (PMID: 16453024), sudden cardiac death (PMID: 23692053), and dilated cardiomyopathy (PMID: 37461109). This variant has also been identified in 23/248792 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

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 03, 2015

The p.Arg689His variant in SCN5A has been previously reported in 6 individuals w ith arrhythmia (3 with Brugada syndrome, 1 with long QT, 1 with VT and mitral va lvular disease, and 1 with progressive conduction disease and episodes of syncop e; Maekawa 2005, Napolitano 2005, Nakajima 2011, Hong 2012, Sottas 2013). In the family with episodes of syncope, the variant segregated with disease in 2 affec ted siblings who had syncope and sudden death and 2 additional family members wi th borderline QT prolongation (Sottas 2013). However, this variant has also been reported in 7/16128 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199473145). In vitro functional studies provide some evidence that the p.Arg689His variant may impact protein fu nction (Hong 2012, Sottas 2013), but these types of assays may not accurately re present biological function. Furthermore, arginine (Arg) at position 689 is not conserved in mammals or evolutionarily distant species, and 7 mammals carry a hi stidine (His) at this position, suggesting that this change may be tolerated. In summary, the clinical significance of the p.Arg689His variant is uncertain. -

Brugada syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

SCN5A-Related Arrhythmias

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 07, 2019

Several studies have reported patients with arrhythmias who are heterozygous for the SCN5A c.2066G>A (p.Arg689His) missense variant (Maekawa et al., 2005; Napolitano et al., 2005; Nakajima et al., 2011; Hong et al., 2012). Additionally, a three-generation family was reported by Sottas et al. (2013) in which two twin girls suffered sudden cardiac death from their first syncope at ages four and five. Their sister had her first syncope at five months and has a pacemaker. All three sisters are heterozygous for the p.Arg689His variant, as are their mother and maternal grandmother, who have prolonged QT intervals on ECG. The p.Arg689His variant has been found in three of 1,276 healthy controls and is reported at a frequency of 0.000434 in the South Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg689His variant is classified as a variant of unknown significance but suspicious for pathogenicity for SCN5A-related arrhythmias. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

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

Oct 13, 2021

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2024

The p.R689H variant (also known as c.2066G>A), located in coding exon 13 of the SCN5A gene, results from a G to A substitution at nucleotide position 2066. The arginine at codon 689 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in individuals with Brugada syndrome, long QT syndrome, and other arrhythmias (Maekawa K et al. Ann. Hum. Genet., 2005 Jul;69:413-28; Napolitano C et al. JAMA, 2005 Dec;294:2975-80; Nakajima T et al. Int Heart J, 2011;52:27-31; Hong K et al. Eur. J. Hum. Genet., 2012 Nov;20:1189-92). In addition, this variant was reported in twins with sudden cardiac death, a sibling with progressive cardiac conduction disease, and two reportedly asymptomatic relatives (Sottas V et al. J. Cardiovasc. Electrophysiol., 2013 Sep;24:1037-46). In multiple assays testing SCN5A function, this variant showed functionally normal and functionally abnormal results (Sottas V et al. J. Cardiovasc. Electrophysiol., 2013 Sep;24:1037-46; Hong K et al. Eur. J. Hum. Genet., 2012 Nov;20:1189-92). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

CardioboostCm

Benign

0.0092

BayesDel_addAF

Benign

-0.0043

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

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

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.27

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

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.10

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

MetaSVM

Uncertain

0.023

MutationAssessor

Benign

0.71

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

MutationTaster

Benign

0.83

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

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.1

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

REVEL

Uncertain

0.58

Sift

Benign

0.15

T;T;T;T;D;T;T;D;D

Sift4G

Benign

0.083

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

Polyphen

0.0010

B;B;.;B;.;B;B;.;.

Vest4

0.19

MVP

0.98

MPC

0.43

ClinPred

0.017

GERP RS

2.0

Varity_R

0.037

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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