rs199473072

Positions:

chr3-38613773-G-A

Variant summary

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

The ENST00000423572.7(SCN5A):c.673C>T(p.Arg225Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000311 in 1,609,370 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 12/21 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. R225Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 1 hom. )

Consequence

SCN5A
ENST00000423572.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13U:1O:1

Conservation

PhyloP100: 8.02

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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 11 uncertain in ENST00000423572.7

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-38613772-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2203341.Status of the report is criteria_provided_single_submitter, 1 stars.

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, 0.964

PP5

Variant 3-38613773-G-A is Pathogenic according to our data. Variant chr3-38613773-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38613773-G-A is described in Lovd as [Pathogenic]. Variant chr3-38613773-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_000335.5 linkuse as main transcript	c.673C>T	p.Arg225Trp	missense_variant	6/28	ENST00000423572.7	NP_000326.2
SCN5A	NM_001099404.2 linkuse as main transcript	c.703+202C>T		intron_variant		ENST00000413689.6	NP_001092874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000423572.7 linkuse as main transcript	c.673C>T	p.Arg225Trp	missense_variant	6/28	1	NM_000335.5	ENSP00000398266	A1	Q14524-2
SCN5A	ENST00000413689.6 linkuse as main transcript	c.703+202C>T		intron_variant		5	NM_001099404.2	ENSP00000410257	P4

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

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

GnomAD3 exomes

AF:

0.0000124

AC:

AN:

242066

Hom.:

AF XY:

0.0000153

AC XY:

AN XY:

131140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000592

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000342

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000261

AC:

AN:

1457170

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

724356

show subpopulations

Gnomad4 AFR exome

AF:

0.0000898

Gnomad4 AMR exome

AF:

0.0000453

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000588

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.000265

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

Alfa

AF:

0.0000341

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 225 of the SCN5A protein (p.Arg225Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of autosomal dominant SCN5A-related conditions (PMID: 12574143, 19251209, 19606473, 19716085, 20031634, 20129283, 22885917). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68032). 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: 12574143, 25624448). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg225 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24815523, 26022185). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 06, 2023	PP3, PM1, PM2, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2021	Reported in association with Long QT syndrome, Brugada syndrome, sudden arrhythmia death syndrome (SADS), and other conduction disorders (Bezzina et al., 2003; Kapplinger et al., 2009; Meregalli et al., 2009; Probst et al., 2009; Kapplinger et al., 2010; Lahrouchi et al., 2017); Observed with a nonsense variant on the opposite allele (in trans) in two infant siblings with severe conduction disease and wide QRS-complexes (Bezzina et al., 2003); Published functional studies demonstrated R225W results in a significant reduction in sodium current amplitude and an alteration in gating pore current, indicating gain of function (Bezzina et al., 2003; Moreau et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic/likely pathogenic (ClinVar Variant ID# 68032; ClinVar); This variant is associated with the following publications: (PMID: 26916278, 24136861, 31477192, 31981491, 25637381, 24573164, 25624448, 12574143, 19251209, 19716085, 20031634, 20129283, 29167113, 21167004, 28449774, 16922724, 29728395, 31125670, 30193851, 32048431, 32536774, 30847666, 31447099, 33131149, 26582918, 32746448) -

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:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS3_Moderate+PS4_Supporting+PP4+PM5_Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 17, 2021	- -

Long QT syndrome 3

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	May 24, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jul 05, 2017	This c.673C>T (p.Arg225Trp) variant has been reported in 7 patients with Brugada syndrome from 2 families [PMID 19251209]. This variant was also reported in two siblings with severe conduction disease compound heterozygous for this variant and p.Trp146* variant [PMID 12574143]. The mother however, who was a carrier for this variant, was clinically asymptomatic with normal ECG. Functional assay showed that this variant affects the sodium channel voltage gating. Variants affecting the same amino acid (p.Arg225Gln and p.Arg225Pro) have been reported in additional patients with arrythmias indicating the functional importance of this amino acid and its position [PMID 16922724, 26733869]. This variant was reported in one heterozygous individuals from Europe (http://exac.broadinstitute.org/variant/3-38655264-G-A). This variant is highly conserved in mammals. While not validated for clinical use, computer-based algorithms predict this p.Arg225Trp change to be deleterious. It is thus classified as a pathogenic variant. -

Cardiac arrhythmia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 11, 2023	This missense variant replaces arginine with tryptophan at codon 225 of the SCN5A protein. This variant is found within a highly conserved region of the transmembrane domain DI. Rare nontruncating variants in this region (a.a.132-410) have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). Functional studies have shown that this variant causes a significant reduction in sodium current (PMID: 12574143, 19251209, 25624448). This variant has been reported in in over ten individuals affected with Brugada syndrome (PMID: 19251209, 20031634, 36516610). This variant has been observed in compound heterozygous state with p.Trp156* in the same gene in two siblings affected with severe, early-onset conduction disease (PMID: 12574143). It has been shown that this variant segregates with disease in some of these families (PMID: 12574143, 19251209, 20031634). This variant has also been reported in individuals suspected of having Brugada syndrome (PMID: 20129283) or long QT syndrome (PMID: 19716085), as well as in an individual affected with sudden arrhythmic death syndrome (PMID: 34620408). This variant has been identified in 6/273472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 07, 2024	Variant summary: SCN5A c.673C>T (p.Arg225Trp) 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 1.2e-05 in 242066 control chromosomes. c.673C>T has been reported in the literature in multiple individuals affected with autosomal dominant SCN5A-related conditions (examples: Probst_2009) These data indicate that the variant is very likely to be associated with disease. Experimental studies have shown that this missense change disrupts the normal function of the protein (examples: Moreau_2015, Strege_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29167113, 25624448, 20031634). ClinVar contains an entry for this variant (Variation ID: 68032). Based on the evidence outlined above, the variant was classified as pathogenic. -

SCN5A-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Aug 16, 2019

ACMG classification criteria: PS3, PM1, PM6 -

Brugada syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 09, 2024

This missense variant replaces arginine with tryptophan at codon 225 of the SCN5A protein. This variant is found within a highly conserved region of the transmembrane domain DI. Rare nontruncating variants in this region (a.a.132-410) have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). Multiple functional studies have shown that this variant causes a significant reduction in sodium current (PMID: 12574143, 19251209, 25624448). One study using human-induced pluripotent stem cell-cardiomyocytes was inconclusive with regard to the effect of this variant, because the cells used mainly expressed a fetal isoform that lacks an exon from an adult isoform, in which this variant is located (PMID: 35394010). This variant has been reported in at least 7 unrelated individuals affected with Brugada syndrome (PMID: 19251209, 20031634, 20129283, 36516610) and in 2 infant siblings affected with severe conduction disease (compound heterozygous with p.Trp156* in the same gene; PMID: 12574143). This variant has been shown to segregate with disease in at least 9 individuals from 3 unrelated families (PMID: 12574143, 19251209, 20031634). It has also been reported in individuals with long QT syndrome (PMID: 19716085) and sudden arrhythmic death syndrome (PMID: 34620408). This variant has been identified in 6/273472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 18, 2023

The p.R225W pathogenic mutation (also known as c.673C>T), located in coding exon 5 of the SCN5A gene, results from a C to T substitution at nucleotide position 673. The arginine at codon 225 is replaced by tryptophan, an amino acid with dissimilar properties, and is located in the DI-S4 transmembrane region. This variant was previously described in conjunction with another SCN5A alteration in compound heterozygous siblings, both of whom were diagnosed with severe cardiac conduction disease after birth. One of these siblings also developed severe dilated cardiomyopathy (DCM) and died at 1 year of age (Bezzina CR et al. Circ Res. 2003;92:159-68). In another family, this variant was reported in multiple individuals with progressive cardiac conduction disease (PCCD) and/or Brugada syndrome (BrS), although a relative negative for this alteration also exhibited PCCD (Probst V et al. Circ Cardiovasc Genet. 2009;2:552-7). This alteration has also been reported in sudden cardiac death, BrS, and LQTS cohorts (Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Kapplinger JD et al. Heart Rhythm. 2010;7:33-46; Lahrouchi N et al. J. Am. Coll. Cardiol. 2017 May;69(17):2134-2145). Multiple in vitro functional analyses indicate that this variant impacts protein function (Bezzina CR et al. Circ. Res. 2003;92:159-68; Moreau A et al. J Gen Physiol. 2015;145:93-106; Strege PR et al. Am. J. Physiol. Gastrointest. Liver Physiol. 2018;314:G494-G503). In addition, based on internal structural assessment, this alteration is predicted to disrupt the voltage sensing motif in voltage sensing domain 1 (Jiang D et al. Cell. 2020;01;180(1):122-134.e10). Other alterations affecting the same amino acid, p.R225Q (c.674G>A) and p.R225P (c.674G>C), have been reported in patients with complex arrhythmias and multifocal ventricular ectopy (Millat G et al. Clin Genet. 2006;70:214-27; Beckermann TM et al. Heart Rhythm. 2014;11:1446-53). 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. -

Conduction system disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Congenital long QT syndrome

Other:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

CardioboostCm

Uncertain

0.61

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

.;D;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.5

H;H;.

MutationTaster

Benign

1.0

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

PROVEAN

Pathogenic

-7.8

D;D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.97

MVP

0.99

ClinPred

0.97

GERP RS

4.3

Varity_R

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.31

Position offset: -30

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