chr3-38606710-G-A

Position:

chr3-38606710-G-A

Variant summary

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

The NM_000335.5(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. 13/22 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_000335.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.23

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:

SCN5A (HGNC:):

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 intramembrane_region Pore-forming (size 24) in uniprot entity SCN5A_HUMAN there are 9 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 chr3-38606709-C-T is described in Lovd as [Pathogenic].

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 4.8279 (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, 0.993

PP5

Variant 3-38606710-G-A is Pathogenic according to our data. Variant chr3-38606710-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38606710-G-A is described in Lovd as [Pathogenic]. Variant chr3-38606710-G-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.1099C>T	p.Arg367Cys	missense_variant	9/28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 linkuse as main transcript	c.1099C>T	p.Arg367Cys	missense_variant	9/28	ENST00000423572.7	NP_000326.2	Q14524-2Q86V90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.1099C>T	p.Arg367Cys	missense_variant	9/28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 linkuse as main transcript	c.1099C>T	p.Arg367Cys	missense_variant	9/28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

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

GnomAD3 exomes

AF:

0.00000804

AC:

AN:

248818

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135012

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 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:

0.00000274

AC:

AN:

1461476

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726996

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

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

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2024	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Aug 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 01, 2023	For these reasons, this variant has been classified as Pathogenic. 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. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) indicates that this missense variant is expected to disrupt SCN5A function. ClinVar contains an entry for this variant (Variation ID: 67633). This missense change has been observed in individuals with Brugada syndrome, primary electrical disease and unexplained cardiac arrest (PMID: 20129283, 21273195, 28341588, 28600387). This variant is present in population databases (rs199473097, gnomAD 0.006%). 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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 21, 2024	PP3, PM1, PM2, PM5, PS3_moderate, PS4_moderate -

Congenital long QT syndrome

Pathogenic:1Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 27, 2023	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. -
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 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. -

SCN5A-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

DASA

Feb 05, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Brugada syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 22, 2021

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 23, 2024

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

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

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;.;.;.

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

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

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