3-38606682-C-T

Position:

chr3-38606682-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_001099404.2(SCN5A):c.1127G>A(p.Arg376His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,106 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R376C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 2.06

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 17 ACMG points.

PM1

In a helix (size 11) in uniprot entity SCN5A_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_001099404.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-38606683-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67638.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=2, not_provided=1}.

PP2

Missense variant where missense usually causes diseases, SCN5A

PP3

MetaRNN computational evidence supports a deleterious effect, 0.915

PP5

Variant 3-38606682-C-T is Pathogenic according to our data. Variant chr3-38606682-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38606682-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.1127G>A	p.Arg376His	missense_variant	9/28	ENST00000413689.6
SCN5A	NM_000335.5 linkuse as main transcript	c.1127G>A	p.Arg376His	missense_variant	9/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.1127G>A	p.Arg376His	missense_variant	9/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.1127G>A	p.Arg376His	missense_variant	9/28	1	NM_000335.5	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000808

AC:

AN:

247596

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134378

show subpopulations

Gnomad AFR exome

AF:

0.0000654

Gnomad AMR exome

AF:

0.0000291

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460870

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726652

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000330

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 26, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2023	Published functional studies demonstrate this variant results in a significant reduction of the inward sodium current (Rossenbacker et al., 2004; Shinlapawittayatorn et al., 2011; Detta et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17512504, 20129283, 28341781, 34461752, 15851228, 23414114, 25194972, 18378609, 16344400, 23671135, 27930701, 21840964, 31737537, 30193851, 30662450, 29709101, 33164571, 33131149, 30203441, 34495297, 24295898) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 17, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 376 of the SCN5A protein (p.Arg376His). This variant is present in population databases (rs199473101, gnomAD 0.004%). This missense change has been observed in individuals with Brugada syndrome (PMID: 15851228, 16344400, 18378609, 20129283, 23671135, 25194972, 27930701, 28341781). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67639). 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: 15851228, 21840964, 24295898). For these reasons, this variant has been classified as 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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 12, 2021

- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2024

The p.R376H variant (also known as c.1127G>A), located in coding exon 8 of the SCN5A gene, results from a G to A substitution at nucleotide position 1127. The arginine at codon 376 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in multiple individuals with Brugada syndrome (BrS; Rossenbacker T et al. Heart Rhythm. 2004;1(5):610-5; Frustaci A et al. Circulation. 2005;112(24):3680-7; Kapplinger JD et al. Heart Rhythm. 2010;7(1):33-46). It has also been identified in an individual with atrial fibrillation (Darbar D et al. Circulation. 2008;117(15):1927-35) and in families with a history of sudden death (Papadakis M et al. Circ Arrhythm Electrophysiol. 2013;6(3):588-96; Wong LC et al. Circ Arrhythm Electrophysiol. 2014;7(5):800-6). Additionally, p.R376H has been shown to disrupt protein function, resulting in reduced sodium channel current (Rossenbacker T et al. Heart Rhythm 2004;1(5):610-5; Shinlapawittayatorn K et al. Heart Rhythm 2011; 8(3):455-62; Detta N et al. Int. J. Cardiol. 2014; 170(3):e63-5; Peters CH et al. Mol. Biol. 2016;120(1-3):77-88). This amino acid position is not well 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. -

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

Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center

Nov 11, 2021

The c.1127G>A variant in theSCN5A gene is a heterozygous missense variant, which results in the substitution of the highly conserved arginine residue at the 376 position to histidine p.(Arg376His). The following criteria was used in classifying this variant: This variant localizes to coding exon 9 of the SCN5A gene (27 exons in total;NM_001160161.2). Functional studies of the variant showed reduction of the inward sodium current in cells expressing the p.Arg376His variant compared with the wildtype, which is consistent with a Brugada syndrome pattern (PMID: 24295898). This variant has been observed in the Genome Aggregation Database (gnomAD) at a very low frequency (2/247,596, 0 homozygotes), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in the literature segregating with disease in one family affected with Brugada syndrome/conduction disease (PMID: 15851228), in several individuals affected with Brugada syndrome (PMID: 16344400, 28341781), in individuals referred for Brugada genetic testing (PMID: 20129283), atrial fibrillation (PMID: 18378609), hypertrophic cardiomyopathy (PMID: 27930701), in individuals referred for Brugada genetic testing (PMID: 20129283), and in individuals who suffered sudden unexplained death (PMID: 25194972, 23671135). -

Cardiac arrhythmia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Aug 08, 2023

This missense variant replaces arginine with histidine at codon 376 of the SCN5A protein. This variant is found within the highly conserved pore-forming region of transmembrane domain DI (a.a. 277-389). Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). Functional studies have shown that this variant significantly reduces sodium channel currents (PMID: 15851228, 21840964, 24295898, 26713557). This variant has shown a highly variable phenotypic presentation ranging from Brugada syndrome to conduction disease in 9 members from a single family (PMID: 15851228). This variant has been reported in multiple other individuals affected with Brugada syndrome or referred for Brugada syndrome genetic testing (PMID: 16344400, 20129283, 28341781, 29709101) in an individual affected with atrial fibrillation (PMID: 18378609) and in individuals affected with sudden death (PMID: 23671135, 25194972, 27930701). This variant has been identified in 2/247596 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Brugada 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 Brugada syndrome in the following publications (PMID:15851228;PMID:16344400;PMID:20129283;PMID:18378609). 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

Uncertain

0.36

CardioboostCm

Uncertain

0.29

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.77

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.91

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

MetaSVM

Pathogenic

1.0

MutationTaster

Benign

0.99

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

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.5

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

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0080

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

Sift4G

Uncertain

0.0060

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

Polyphen

0.99

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

Vest4

0.68

MVP

0.94

MPC

1.3

ClinPred

0.98

GERP RS

4.7

Varity_R

0.34

gMVP

0.94

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