3-38586037-C-T

Variant names:

• chr3-38586037-C-T
• rs199473584
• NM_001099404.2:c.2441G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_001099404.2(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. 15/26 in silico tools predict a damaging 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 Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:1 O:1
• Conservation: PhyloP100: 7.91
• Publications: 25 publications found

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 Gene-Disease associations (from GenCC):

• Brugada syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Brugada syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1E

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• sick sinus syndrome 1

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial heart block, type 1A

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• atrial standstill

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sick sinus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal familial ventricular fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001099404.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38586038-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 67731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId 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	c.2441G>A	p.Arg814Gln	missense_variant	Exon 16 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.2441G>A	p.Arg814Gln	missense_variant	Exon 16 of 28	ENST00000423572.7	NP_000326.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152038 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000242 AC: 6 AN: 247846 AF XY: 0.00000743

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1458822 Hom.: 0 Cov.: 36 AF XY: 0.0000193 AC XY: 14 AN XY: 725100

African (AFR) AF: 0.0000598 AC: 2 AN: 33434

American (AMR) AF: 0.0000224 AC: 1 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39636

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1109422

Other (OTH) AF: 0.0000332 AC: 2 AN: 60260

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152038 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74262

African (AFR) AF: 0.00 AC: 0 AN: 41386

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000175 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

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. -

Jul 28, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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). -

Cardiovascular phenotype Pathogenic:2

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. -

Jan 03, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4_mod, PM1, PM2, PM5, PP2, PP3 -

Brugada syndrome Pathogenic:1 Other:1

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. -

-

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. -

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 -

Cardiac arrhythmia Pathogenic:1

Jun 18, 2024

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. -

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. -

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
CardioboostArm	Pathogenic	1.0
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.8	.;H;.;.;.;H;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.89	D
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	D
GERP RS		4.4
Varity_R		0.93
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199473584; hg19: chr3-38627528;