rs199473097

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001099404.2(SCN5A):c.1099C>T(p.Arg367Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 15/24 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. R367H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 5.23

Publications

16 publications found

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 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

SCN5A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain 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 chr3-38606709-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 9390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 3-38606710-G-A is Pathogenic according to our data. Variant chr3-38606710-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 67633.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.1099C>T	p.Arg367Cys	missense_variant	Exon 9 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 link	c.1099C>T	p.Arg367Cys	missense_variant	Exon 9 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 link	c.1099C>T	p.Arg367Cys	missense_variant	Exon 9 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7 link	c.1099C>T	p.Arg367Cys	missense_variant	Exon 9 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000804

AC:

AN:

248818

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000274

AC:

AN:

1461476

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726996

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.0000447

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111828

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74376

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68050

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Nov 07, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect as this variant results in reduction of the sodium current (PMID: 19251209); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19716085, 19251209, 21273195, 24136861, 20129283, 28341588, 28600387, 30662450, 22581653, 11823453, 32533946, 25904541, 30203441, 33131149, 29709244, 35305865, 12106943, 15028074, 22028457) -

Feb 21, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PM1, PM2, PM5, PS3_moderate, PS4_moderate -

Aug 30, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 367 of the SCN5A protein (p.Arg367Cys). This variant is present in population databases (rs199473097, gnomAD 0.006%). This missense change has been observed in individuals with Brugada syndrome, primary electrical disease and unexplained cardiac arrest (PMID: 20129283, 21273195, 28341588, 28600387). ClinVar contains an entry for this variant (Variation ID: 67633). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 32533946) indicates that this missense variant is expected to disrupt SCN5A function with a positive predictive value of 95%. This variant disrupts the p.Arg367 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11823453, 20129283). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Congenital long QT 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 Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Apr 27, 2023

All of Us Research Program, National Institutes of Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1099C>T (p.Arg367Cys) variant in the SCN5A gene is located on the exon 9 and is predicted to replace arginine with cysteine at codon 367 (p.Arg367Cys). The variant has been reported in more than 10 unrelated individuals affected with Brugada syndrome or unexplained sudden cardiac arrest (PMID: 21273195, 20129283, 19251209, 22885917, 26538325, 28600387, 28341588). Negative functional impact of the variant was confirmed with the patch clamp experiment (PMID: 32533946, 19251209). This variant is rare in the general population according to gnomAD (3/280212). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.956). Another variant disrupting the same amino acid (p.Arg367His) has been interpreted as pathogenic (ClinVar ID: 9390). Therefore, the c.1099C>T (p.Arg367Cys) variant of SCN5A has been classified as likely pathogenic. -

SCN5A-related disorder

Pathogenic:1

Feb 05, 2022

DASA

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1099C>T;p.(Arg367Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 67633; PMID: 21273195; 20129283; 28600387) - PS4_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Ion_trans) - PM1. This variant is not present in population databases (rs199473097; gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 9390 - c.1100G>A;p.(Arg367His)) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is 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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Brugada syndrome

Pathogenic:1

Feb 22, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg367Cys variant in SCN5A has been reported in at least 5 individuals affected with Brugada syndrome (BrS; Smits 2002 PMID:12106943, Amin 2011 PMID: 21273195, Glazer 2020 PMID: 32533946, in at least 1 family with primary electrical disease (Proost 2017 PMID: 28341588), and in at least 2 individuals with unexplained cardiac arrest (Mellor 2017 PMID: 28600387, Meregalli 2009 PMID: 19251209). Additionally, it has been reported in 2 individuals with suspected BrS that were referred for genetic diagnostic testing (Kapplinger 2009 PMID: 19716085, Kapplinger 2010 PMID: 20129283) and by other clinical laboratories in ClinVar (Variation ID: 67633). This variant has also been identified in 0.006% (2/35330) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro patch clamp assays suggest that this variant results in a complete loss of sodium current (Meregalli 2009 PMID: 19251209, Glazer 2020 PMID: 32533946) and computational prediction tools and conservation analysis are consistent with pathogenicity. Another variant involving this codon (p.Arg367His) has been identified in individuals with disease and is classified as pathogenic by several clinical laboratories in ClinVar. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant SCN5-related disorder. ACMG/AMP Criteria applied: PM5_Supporting, PP3, PM2_Supporting, PS4_Moderate, PS3_Supporting. -

Cardiovascular phenotype

Pathogenic:1

Feb 01, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R367C pathogenic mutation (also known as c.1099C>T), located in coding exon 8 of the SCN5A gene, results from a C to T substitution at nucleotide position 1099. The arginine at codon 367 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the transmembrane-spanning DI-S5/S6 domain. This alteration has been identified in Brugada syndrome cohorts and is reported to co-segregate with disease (Smits JP et al. J. Am. Coll. Cardiol., 2002 Jul;40:350-6; Rodríguez-Mañero M et al. Heart Rhythm, 2016 Mar;13:669-82; Proost D et al. J Mol Diagn, 2017 Mar;pii:S1525-1578). This variant has also been described in a sudden cardiac arrest cohort (Mellor G et al. Circ Cardiovasc Genet, 2017 Jun;10:). This alteration is predicted to result in complete reduction of peak sodium channel current by patch-clamp analysis (Meregalli PG et al. Heart Rhythm, 2009 Mar;6:341-8). Alterations affecting the same amino acid (p.R367H, c.1100G>A and p.R367L, c.1100G>T) have been identified in Brugada syndrome cohorts; the p.R367H alteration has demonstrated absent sodium channel current in several in vitro studies and is reported to co-segregate with disease (Vatta M et al. Hum. Mol. Genet., 2002 Feb;11:337-45; Hong K et al. J. Cardiovasc. Electrophysiol., 2004 Jan;15:64-9; Takehara N et al. J. Intern. Med., 2004 Jan;255:137-42; Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46). This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Cardiac arrhythmia

Pathogenic:1

Jan 23, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SCN5A c.1099C>T (p.Arg367Cys) 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 8e-06 in 248818 control chromosomes (gnomAD). c.1099C>T has been reported in the literature in multiple individuals affected with Brugada syndrome and Long QT syndrome (examples: Amin_2011, Meregalli_2009, Nannenberg_2012). Variant affecting the same amino acid has been classified as pathogenic in ClinVar (p.Arg367His CV ID 9390). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 19716085, 20129283, 22885917, 21273195, 19251209, 24136861, 22373669, 12106943). ClinVar contains an entry for this variant (Variation ID: 67633). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

CardioboostArm

Pathogenic

0.96

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

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

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

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

PhyloP100

5.2

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-7.8

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

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.98

MutPred

0.97

Gain of catalytic residue at L368 (P = 0.0116);Gain of catalytic residue at L368 (P = 0.0116);Gain of catalytic residue at L368 (P = 0.0116);Gain of catalytic residue at L368 (P = 0.0116);Gain of catalytic residue at L368 (P = 0.0116);Gain of catalytic residue at L368 (P = 0.0116);Gain of catalytic residue at L368 (P = 0.0116);Gain of catalytic residue at L368 (P = 0.0116);Gain of catalytic residue at L368 (P = 0.0116);

MVP

0.96

MPC

1.3

ClinPred

1.0

GERP RS

4.7

Varity_R

0.92

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over