3-38606709-C-T

Position:

chr3-38606709-C-T

Variant summary

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

The NM_001099404.2(SCN5A):c.1100G>A(p.Arg367His) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,678 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R367C) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.16

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 helix (size 11) in uniprot entity SCN5A_HUMAN there are 5 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 chr3-38606710-G-A 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 4.7729 (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, 0.988

PP5

Variant 3-38606709-C-T is Pathogenic according to our data. Variant chr3-38606709-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38606709-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.1100G>A	p.Arg367His	missense_variant	9/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 linkuse as main transcript	c.1100G>A	p.Arg367His	missense_variant	9/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.1100G>A	p.Arg367His	missense_variant	9/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.1100G>A	p.Arg367His	missense_variant	9/28	1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461470

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brugada syndrome 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Jun 28, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2002	- -

Brugada syndrome

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Nov 18, 2016	- -
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:11823453;PMID:14687250;PMID:15028074;PMID:19251209;PMID:22028457;PMID:20129283). 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

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2024

The SCN5A c.1100G>A variant is predicted to result in the amino acid substitution p.Arg367His. This variant has been reported in at least 8 unrelated individuals with Brugada syndrome (Hong et al. 2004. PubMed ID: 15520322; Takehara et al. 2004. PubMed ID: 14687250; Kapplinger et al. 2010. PubMed ID: 20129283), in an individual with sudden unexplained death in which the variant was apparently de novo (Vatta et al. 2002. PubMed ID: 11823453), and in an individual with an AV block (Baruteau et al. 2012. PubMed ID: 22899775). The variant was found in 18 individuals in one family, of which 15 had ECGs consistent with Brugada syndrome either at baseline or when treated with a sodium channel blocker (Hong et al. 2004. PubMed ID: 15520322). Functional studies in Xenopus oocytes and in induced pluripotent stem cells indicate this variant results in a loss of channel current (Vatta et al. 2002. PubMed ID: 11823453; Takehara et al. 2004. PubMed ID: 14687250; Selga et al. 2018. PubMed ID: 29024690). Alternate nucleotide changes affecting the same amino acid have been reported in individuals with Brugada syndrome (p.Arg367Leu) and in both Brugada syndrome and Long QT syndrome (p.Arg367Cys) (Kapplinger et al. 2015. PubMed ID: 25904541). This variant has not been reported in a large population database, indicating it is rare. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 16, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 367 of the SCN5A protein (p.Arg367His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Brugada syndrome (PMID: 11823453, 14753626, 17697823, 20129283, 22028457, 22899775, 24529773, 26173111). ClinVar contains an entry for this variant (Variation ID: 9390). 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: 11823453, 21840964, 25348405). 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: 20129283, 21273195). 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. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2023

The p.R367H pathogenic mutation (also known as c.1100G>A), located in coding exon 8 of the SCN5A gene, results from a G to A substitution at nucleotide position 1100. The arginine at codon 367 is replaced by histidine, an amino acid with highly similar properties. This alteration has been described in association with Brugada syndrome, cardiac conduction defects, and sudden death (Vatta M et al. Hum Mol Genet. 2002;11:337-45; Takehara N et al. J Intern Med. 2004;255:137-42). In one study, this alteration was detected in multiple relatives in a family with Brugada syndrome (Hong K et al. J Cardiovasc Electrophysiol. 2004;15:64-9). In several functional in vitro analyses, this alteration has demonstrated adverse effects resulting in absent sodium channel current (Vatta et al, 2002). This variant is 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

Color Diagnostics, LLC DBA Color Health

Mar 21, 2019

This missense variant replaces arginine with histidine at codon 367 in the pore-forming region of transmembrane domain DI of the SCN5A protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental studies have shown that the mutant protein failed to generate sodium current in heterologous expression studies, despite normal channel protein trafficking to the cell membrane (PMID: 11823453, 14687250, 15028074, 22028457, 29024690). This variant has been shown to segregate with disease in a large Spanish family affected with familial Brugada syndrome (PMID: 15028074). This variant has been reported in over ten unrelated individuals affected with or suspected of having Brugada syndrome (PMID: 14753626, 17697823, 20129283, 26173111, 28341781), five individuals affected with sudden death (PMID: 11823453, 15028074, 24529773), two individuals affected with ventricular fibrillation (PMID: 22028457, 28912206), and in an individual affected with isolated atrioventricular block (PMID: 22899775). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at this codon (p.Arg367Cys) is associated with disease, suggesting the importance of this position in the sodium channel function (Clinvar variation ID: 67633). Based on available evidence, this variant is 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

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

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

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

.;M;.;.;.;M;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.9

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

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.90

MutPred

0.95

Gain of catalytic residue at M369 (P = 0.0631);Gain of catalytic residue at M369 (P = 0.0631);Gain of catalytic residue at M369 (P = 0.0631);Gain of catalytic residue at M369 (P = 0.0631);Gain of catalytic residue at M369 (P = 0.0631);Gain of catalytic residue at M369 (P = 0.0631);Gain of catalytic residue at M369 (P = 0.0631);Gain of catalytic residue at M369 (P = 0.0631);Gain of catalytic residue at M369 (P = 0.0631);

MVP

0.99

MPC

1.3

ClinPred

1.0

GERP RS

4.7

Varity_R

0.94

gMVP

0.98

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