rs878855292

Positions:

chr3-38551478-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000335.5(SCN5A):c.4891C>T(p.Arg1631Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,886 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.75

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 17 ACMG points.

PM1

In a transmembrane_region Helical; Name=S4 of repeat IV (size 16) in uniprot entity SCN5A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000335.5

PM2

Very rare variant in population databases, with high coverage;

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, 0.992

PP5

Variant 3-38551478-G-A is Pathogenic according to our data. Variant chr3-38551478-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 242199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38551478-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.4894C>T	p.Arg1632Cys	missense_variant	28/28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 linkuse as main transcript	c.4891C>T	p.Arg1631Cys	missense_variant	28/28	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.4894C>T	p.Arg1632Cys	missense_variant	28/28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 linkuse as main transcript	c.4891C>T	p.Arg1631Cys	missense_variant	28/28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152096

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

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251352

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727182

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:

152096

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74302

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

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2024	Published functional studies showed that p.(R1632C) resulted in loss of sodium channel availability (PMID: 26031372); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26031372, 30193851, 31191357, 33131149, 33221895, 30935997, 33164571, 30203441, 33797273, 26582918, 31928070, 27082542) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 18, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN5A function (PMID: 26031372). 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. ClinVar contains an entry for this variant (Variation ID: 242199). This missense change has been observed in individuals with Brugada syndrome (PMID: 26031372, 27082542, 31191357). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1632 of the SCN5A protein (p.Arg1632Cys). -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 05, 2020

The p.R1632C pathogenic mutation (also known as c.4894C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 4894. The arginine at codon 1632 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the DIV-S4 transmembrane region. This variant has been detected in unrelated probands with Brugada syndrome (BrS) and has shown some segregation with disease in families (Nakajima T et al. Heart Rhythm, 2015 Nov;12:2296-304; García-Molina E et al. Mol Med Rep, 2016 Jun;13:4677-80; Monasky MM et al. Front Physiol, 2019 May;10:666). Internal structural analysis indicates that the arginine impacted by this alteration is part of a highly conserved set of residues that generate a characteristic motif necessary to the function of voltage-sensing channels (Gandhi CS et al. J. Gen. Physiol., 2002 Oct;120:455-63; Starace DM et al. Nature, 2004 Feb;427:548-53). In vitro functional studies have indicated that this variant may impact channel kinetics, and a deep mutational scanning study categorized this alteration as a possible loss of function alteration (Nakajima T et al. Heart Rhythm, 2015 Nov;12:2296-304; Glazer AM et al. Circ Genom Precis Med, 2020 02;13:e002786). Other variants affecting this codon (p.R1632H, c.4895G>A and p.R1632L, c.4895G>T) have also been reported in association with arrhythmias, including Brugada syndrome (Benson DW et al. J. Clin. Invest. 2003;112:1019-28; Batchvarov VN et al. J Electrocardiol;44:308). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

CardioboostCm

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

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

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

5.2

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

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-7.4

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 methylation at R1629 (P = 0.0595);.;.;Gain of methylation at R1629 (P = 0.0595);.;.;.;

MVP

0.98

MPC

1.7

ClinPred

1.0

GERP RS

4.5

Varity_R

0.93

gMVP

1.0

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