3-38586037-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000335.5(SCN5A):c.2441G>A(p.Arg814Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,610,860 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. R814W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U:1O: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 19 ACMG points.

PM1

In a transmembrane_region Helical; Name=S4 of repeat II (size 17) in uniprot entity SCN5A_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000335.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-38586038-G-A is described in Lovd as [Pathogenic].

PP2

Missense variant in the SCN5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. Gene score misZ: 2.7504 (below the threshold of 3.09). Trascript score misZ: 4.8279 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.991

PP5

Variant 3-38586037-C-T is Pathogenic according to our data. Variant chr3-38586037-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.2441G>A	p.Arg814Gln	missense_variant	Exon 16 of 28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.2441G>A	p.Arg814Gln	missense_variant	Exon 16 of 28	ENST00000423572.7	NP_000326.2	Q14524-2Q86V90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 link	c.2441G>A	p.Arg814Gln	missense_variant	Exon 16 of 28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.2441G>A	p.Arg814Gln	missense_variant	Exon 16 of 28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000242

AC:

AN:

247846

Hom.:

AF XY:

0.00000743

AC XY:

AN XY:

134512

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000270

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1458822

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

725100

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000177

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152038

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000715

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

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

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Jul 28, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

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 814 of the SCN5A protein (p.Arg814Gln). This variant is present in population databases (rs199473584, gnomAD 0.005%). This missense change has been observed in individuals with clinical features of autosomal dominant SCN5A-related conditions (PMID: 17442746, 23321620, 26669661, 30847666, 30975432, 31983221, 32659924, 34461752). ClinVar contains an entry for this variant (Variation ID: 67732). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 32533946) did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN5A function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 32533946). This variant disrupts the p.Arg814 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15671429, 24815523, 26733869). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

May 08, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R814Q pathogenic variant in the SCN5A gene has been previously reported in multiple individuals in association with Brugada syndrome (Frigo et al., 2007; Sommariva et al., 2013; Yamagata et al., 2017). Frigo et al. (2007) identified this variant in a homozygous individual with Brugada syndrome, sustained monomorphic ventricular tachycardia, left bundle branch block, and right ventricular abnormalities suggestive of arrhythmogenic right ventricular cardiomyopathy. This individual's parents and all four siblings were heterozygous for the R814Q variant, and both the mother and one sibling had ECG abnormalities suggestive of Brugada syndrome which were characterized by ST-segment elevation with coved type aspect in right precordial leads (Frigo et al., 2007). Additionally, this variant was identified in one Italian individual with Brugada syndrome (Sommarvia et al., 2013), and one Japanese individual with Brugada syndrome who experienced aborted cardiac arrest (Yamagata et al., 2017). This variant has also been reported in three individuals from one family in association with LQTS (Itoh et al., 2016), however, no clinical details regarding the proband or the affected status of the two relatives were described.The R814Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs in the voltage-sensing transmembrane segment (S4) of domain II at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, functional studies in Xenopus oocytes showed that R814Q reduces the net positive charge of the S4 segment, significantly decreases the voltage dependence of activation, and causes alterations in the slopes and mid-points of steady-state inactivation, which indicates this variant impacts both activation and inactivation gating of the sodium channel (Chen et al., 1996). Moreover, a pathogenic missense variant at the same residue (R814W) has been reported in association with SCN5A-related disorders (Olson et al., 2005), supporting the functional importance of this residue. Finally, the R814Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). -

Brugada syndrome

Pathogenic:1Other: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 Brugada syndrome in the following publications (PMID:17442746). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Sep 03, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2441G>A (p.Arg814Gln) variant in SCN5A gene replaces arginine with glutamine at codon 814 of the SCN5A protein. This variant has been reported in individuals affected with Brugada syndrome (PMID: 17442746, 23321620, 28341781, 33221895, 34147702, 36291626). This variant has also been reported in individuals affected with ventricular fibrillation (PMID: 32389048), dilated cardiomyopathy (PMID: 26669661, 31983221, 32659924), noncompaction cardiomyopathy (PMID: 30847666), and in a survivor of sudden cardiac arrest (PMID: 30975432). This variant is located within the highly conserved transmembrane domain DII (a.a. 718-938, PMID:32893267). A different missense variant affecting the same codon (p.Arg814Trp) has been reported as pathogenic/likely pathogenic in ClinVar (ID: 67731). Functional studies have demonstrated this missense variant affects sodium channel function (PMID: 8972392, 32533946). Computational prediction tools suggest a deleterious impact of this variant on SCN5A protein function (REVEL=0.967). This variant is rare (7/279186 chromosomes, 0.0025%) in the general population database (gnomAD). Based on the available evidence, the variant c.2441G>A (p.Arg814Gln) in SCN5A gene is classified as likely pathogenic. -

SCN5A-related disorder

Pathogenic:1

May 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SCN5A c.2441G>A variant is predicted to result in the amino acid substitution p.Arg814Gln. This variant has been reported in individuals with Brugada syndrome (Sommariva et al. 2013. PubMed ID: 23321620; Ciconte et al. 2020. PubMed ID: 33221895; Milman et al. 2021. PubMed ID: 34461752), long QT syndrome (Itoh et al. 2016. PubMed ID: 26669661), dilated cardiomyopathy (DCM) (Mazzarotto et al. 2020. PubMed ID: 31983221; Kolokotronis et al. 2020. PubMed ID: 32659924), noncompaction cardiomyopathy (van Lint et al. 2019. PubMed ID: 30847666), sudden cardiac arrest (Asatryan et al. 2019. PubMed ID: 30975432), and ventricular fibrillation (Hylind et al. 2020. PubMed ID: 32389048). It has also been observed in the homozygous state in an individual with Brugada syndrome, monomorphic ventricular tachycardia, and structural abnormalities of the right ventricle and in the heterozygous state in 2 family members with ECG abnormalities suggestive of Brugada syndrome (Frigo et al. 2007. PubMed ID: 17442746). In vitro experimental studies indicate that this variant significantly alters sodium channel function (Chen et al. 1996. PubMed ID: 8972392; Glazer et al. 2020. PubMed ID: 32533946). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD. Another missense variant at the same amino acid residue (p.Arg814Trp) has been reported to be disease-causing in individuals with cardiomyopathy and/or arrhythmia and has been shown to be functionally deleterious (Olson et al. 2005. PubMed ID: 15671429; Nguyen et al. 2008. PubMed ID: 18048769; Beckermann et al. 2014. PubMed ID: 24815523). Taken together, the p.Arg814Gln variant is interpreted as likely pathogenic. -

Long QT syndrome 3

Pathogenic:1

Jul 17, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3,PM5 -

Cardiovascular phenotype

Pathogenic:1

Aug 23, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R814Q variant (also known as c.2441G>A), located in coding exon 15 of the SCN5A gene, results from a G to A substitution at nucleotide position 2441. The arginine at codon 814 is replaced by glutamine, an amino acid with highly similar properties. This alteration was reported in homozygous state in an individual with Brugada syndrome (BrS), and segregated with the disease in his affected mother and brother who were heterozygous for this alteration (Frigo G et al. Europace, 2007 Jun;9:391-7). This alteration has also described in cohorts with BrS (Sommariva E et al. Eur. J. Hum. Genet., 2013 Sep;21:911-7, Yamagata K et al. Circulation, 2017 Jun;135:2255-2270), long QT syndrome (Itoh H et al. Eur. J. Hum. Genet., 2016 Aug;24:1160-6), cardiac arrest/ventricular fibrillation (Asatryan B. Am J Cardiol. 2019 06;123(12):2031-2038; Hylind RJ. J Am Heart Assoc. 2020 05;9(10):e016322), and cardiomyopathy (van Lint FHM. Neth Heart J. 2019 Jun;27(6):304-309; Mazzarotto F. Circulation. 2020 02;141(5):387-398). Internal structural analysis revealed that this alteration is disruptive to the voltage sensor motif. Consistently, in vitro studies showed that this alteration would affect channel activity (Chen LQ et al. J. Gen. Physiol., 1996 Dec;108:549-56). 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;C4551804:Brugada syndrome 1

Pathogenic:1

Aug 22, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.2441G>A (p.Arg814Gln) variant in exon 16 of the SCN5A gene results in an amino acid change at residue 814 of an arginine to a glutamine. This variant has been observed in patients with Brugada syndrome and long QT syndrome (PMID: 23321620, 28341781, 26669661) and has also been observe in a homozygous state in one family (PMID: 17442746). This variant is rarely observed in general population databases and functional studies have shown an effect on steady state inactivation (PMID: 8972392). Therefore, the c.2441G>A (p.Arg814Gln) variant in the SCN5A gene is classified as likely pathogenic. -

Cardiac arrhythmia

Pathogenic:1

Dec 07, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 814 of the SCN5A protein. This variant is found within the highly conserved transmembrane domain DII (a.a. 718-938). Rare non-truncating 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 missense variant affects sodium channel function (PMID: 8972392, 32533946, doi:10.1161/circ.118.suppl_18.S_1485). This variant has been reported in eight unrelated individuals affected with Brugada syndrome (PMID: 17442746, 23321620, 28341781, 33221895, 34147702, 36291626, ClinVar SCV000256650.2, doi:10.1161/circ.118.suppl_18.S_1485). This variant has also been reported in individuals affected with ventricular fibrillation (PMID: 32389048), dilated cardiomyopathy (PMID: 26669661, 31983221, 32659924), noncompaction cardiomyopathy (PMID: 30847666), and in a survivor of sudden cardiac arrest (PMID: 30975432). This variant has been identified in 7/279186 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon (p.Arg814Trp) is associated with disease (ClinVar variation ID 67731), suggesting that arginine at this position is important for the protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

not specified

Uncertain:1

Feb 03, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

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

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

4.8

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

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-4.0

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

Uncertain

0.024

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

Polyphen

1.0

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

Vest4

0.99

MutPred

0.97

Loss of MoRF binding (P = 0.0469);Loss of MoRF binding (P = 0.0469);Loss of MoRF binding (P = 0.0469);Loss of MoRF binding (P = 0.0469);Loss of MoRF binding (P = 0.0469);Loss of MoRF binding (P = 0.0469);Loss of MoRF binding (P = 0.0469);Loss of MoRF binding (P = 0.0469);Loss of MoRF binding (P = 0.0469);

MVP

1.0

MPC

1.2

ClinPred

1.0

GERP RS

4.4

Varity_R

0.93

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.40

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.40

Position offset: -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