rs199473220

Positions:

chr3-38562422-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_001099404.2(SCN5A):c.3956G>T(p.Gly1319Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000385 in 1,608,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 7.91

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 Pathogenic. Variant got 10 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 16) in uniprot entity SCN5A_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_001099404.2

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 3-38562422-C-A is Pathogenic according to our data. Variant chr3-38562422-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67838.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=9, not_provided=1, Uncertain_significance=1, Pathogenic=2}. Variant chr3-38562422-C-A is described in Lovd as [Pathogenic]. Variant chr3-38562422-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.3956G>T	p.Gly1319Val	missense_variant	22/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 linkuse as main transcript	c.3953G>T	p.Gly1318Val	missense_variant	22/28	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.3956G>T	p.Gly1319Val	missense_variant	22/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.3953G>T	p.Gly1318Val	missense_variant	22/28	1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000420

AC:

AN:

238270

Hom.:

AF XY:

0.0000465

AC XY:

AN XY:

129124

show subpopulations

Gnomad AFR exome

AF:

0.000139

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:

0.0000739

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000385

AC:

AN:

1456110

Hom.:

Cov.:

AF XY:

0.0000415

AC XY:

AN XY:

723674

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000505

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000478

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000238

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:8

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2024	Identified in two presumably unrelated probands with DCM and cardiac conduction disease; also present in an adult child of each proband, both of whom had at least a reduced left ventricular ejection fraction (PMID: 25179549, 28790152); Published functional studies demonstrate this variant alters sodium channel gating properties and reduces the sodium current, which is consistent with a Brugada syndrome phenotype (PMID: 17854786); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(G1318V); This variant is associated with the following publications: (PMID: 23414114, 19843921, 12106943, 24400668, 24573164, 19889341, 20129283, 21273195, 19251209, 24951569, 22373669, 30609406, 30662450, 29759671, 25904541, 30291343, 30847666, 31447099, 32377377, 33131149, 22581653, 33087929, 29709244, 33164571, 34135346, 34461752, 30203441, 34697415, 25179549, 28790152, 17854786, 20646679, 37061847) -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Nov 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1319 of the SCN5A protein (p.Gly1319Val). This variant is present in population databases (rs199473220, gnomAD 0.009%). This missense change has been observed in individuals with autosomal dominant SCN5A-related conditions (PMID: 17854786, 24951569, 25179549, 25904541, 28790152; Invitae). This variant is also known as G1318V. ClinVar contains an entry for this variant (Variation ID: 67838). 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 disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 17854786). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 15, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Brugada syndrome

Pathogenic:2Other: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 Brugada syndrome in the following publications (PMID:12106943;PMID:17854786;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 28, 2023	This missense variant replaces glycine with valine at codon 1319 of the SCN5A protein. This variant is also known as p.Gly1318Val in the literature based on a different NM_000335 transcript. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the transmembrane domain III. Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes a significant reduction in sodium current (PMID: 17854786, 19251209). This variant has been reported in over ten unrelated individuals affected with Brugada syndrome (PMID: 12106943, 17854786, 19251209, 21273195, 24951569, 29759671, 30847666, 32893267, 36516610, ClinVar SCV000291807.6), in an individual affected with long QT syndrome (PMID: 32893267), and in two individuals affected with progressive cardiac conduction disorders (PMID: 30059973). This variant has been shown to segregates with disease in four first-degree relatives from two families affected with cardiac conduction disease and cardiomypoathy (PMID: 25179549, 28790152). This variant has been identified in 11/269654 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 31, 2018	proposed classification - variant undergoing re-assessment, contact laboratory -

Brugada syndrome (shorter-than-normal QT interval)

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jul 29, 2021

Variant summary: SCN5A c.3956G>T (p.Gly1319Val) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-05 in 238270 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in SCN5A causing Brugada Syndrome (4.2e-05 vs 0.00017), allowing no conclusion about variant significance. c.3956G>T has been reported in the literature in individuals affected with or suspected of Brugada Syndrome (example: Amin_2011, Casini_2007, Kapplinger_2010, Adler_2016) as well as in other in individuals of various cardiac phenotypes (example: Tadros_2017, Meregalli_2009). The variant was also reported in a proband and his son with dilated cardiomyopathy (Golbus_2014) as well as in a mother with reduced left ventricular ejection fraction and frequent ventricular ectopic beats and in her son with possible Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). The son also carried another LMNA variant (Hoorntje_2017). These data indicate that the variant is likely to be associated with disease. In an in vitro functional study, the variant was shown to enhance slow inactivation of SCN5A channel (Casini_2007). However, another in vitro study, co-expressing the wild-type channel and the variant report no reduction in channel current densities (Hoshi_2014). Five ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 10, 2021

- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2024

The p.G1319V variant (also known as c.3956G>T), located in coding exon 21 of the SCN5A gene, results from a G to T substitution at nucleotide position 3956. The glycine at codon 1319 is replaced by valine, an amino acid with dissimilar properties. This variant has been previously reported in multiple affected individuals with confirmed or suspected Brugada syndrome or other arrhythmia phenotypes (Casini S et al. Cardiovasc Res. 2007;76(3):418-29; Meregalli PG et al. Heart Rhythm. 2009;6(3):341-8; Kapplinger JD et al. Heart Rhythm. 2010;7(1):33-46; van der Werf C et al. Heart Rhythm. 2010;7(10):1383-9; Amin AS et al. Europace. 2011;13(7):968-75), and was also reported in an adult male with dilated cardiomyopathy (DCM) and arrhythmia, and in his son who had signs of DCM (Golbus JR et al. Circ Cardiovasc Genet. 2014;7(6):751-9 (reported as p.G1318V)). One study reported that this alteration resulted in abnormal ion channel function (Casini S et al. Cardiovasc Res. 2007;76(3):418-29), while a second study found no impact on sodium current density when co-expressed with wild-type channels (Hoshi M et al. Circ Cardiovasc Genet. 2014;7(2):123-31). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Long QT syndrome 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Apr 04, 2017

The c.3956G>T (p.Gly1319Val) variant has been reported in several patients with Brugada syndrome [PMID 12106943, 19251209, 21273195]. Functional assays showed that this variant contributes to a reduction in sodium currents [PMID 17854786]. This variant was observed in only one individual at the heterozygous state in the ExAC population database (http://exac.broadinstitute.org/variant/3-38603913-C-A).This variant is conserved in mammals and while not clinically validated, computer-based algorithms (SIFT and Polyphen-2) predict this p.Gly1319Val change to be deleterious. This variant is thus classified as pathogenic. Pathogenic variants in SCN5A are also considered medically actionable [ACMG 59, PMID 27854360] -

Cardiac arrhythmia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 24, 2023

This missense variant replaces glycine with valine at codon 1319 of the SCN5A protein. This variant is also known as p.Gly1318Val in the literature based on a different NM_000335 transcript. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the transmembrane domain III. Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes a significant reduction in sodium current (PMID: 17854786, 19251209). This variant has been reported in over ten unrelated individuals affected with Brugada syndrome (PMID: 12106943, 17854786, 19251209, 21273195, 24951569, 29759671, 30847666, 32893267, 36516610, 37061847, ClinVar SCV000291807.6), in an individual affected with long QT syndrome (PMID: 32893267), and in two individuals affected with progressive cardiac conduction disorders (PMID: 30059973). This variant has been shown to segregates with disease in four first-degree relatives from two families affected with cardiac conduction disease and cardiomypoathy (PMID: 25179549, 28790152). This variant has been identified in 11/269654 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

CardioboostCm

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

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

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

5.3

.;.;.;.;.;H;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-8.0

D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D;D

Polyphen

1.0

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

Vest4

0.97

MVP

0.99

MPC

1.6

ClinPred

1.0

GERP RS

4.0

Varity_R

0.99

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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