rs745435760

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP2PP3_Moderate

The NM_001099404.2(SCN5A):c.3067C>T(p.Arg1023Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,736 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1023H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 1 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 3.53

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 Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-38581091-C-T is described in Lovd as [Pathogenic].

PP2

Missense variant where missense usually causes diseases, SCN5A

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.3067C>T	p.Arg1023Cys	missense_variant	17/28	ENST00000413689.6
SCN5A	NM_000335.5 linkuse as main transcript	c.3067C>T	p.Arg1023Cys	missense_variant	17/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.3067C>T	p.Arg1023Cys	missense_variant	17/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.3067C>T	p.Arg1023Cys	missense_variant	17/28	1	NM_000335.5	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152146

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000202

AC:

AN:

247718

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134572

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000894

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461590

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000378

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000278

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2020	Reported in association with Brugada syndrome (Matsumura et al., 2017); Reported in an individual with recorded ventricular fibrillation as well as histology studies that showed myocardial abnormalities (Watanabe et al., 2013); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 574312; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29202755, 23168001, 22407026) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 20, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1023 of the SCN5A protein (p.Arg1023Cys). This variant is present in population databases (rs745435760, gnomAD 0.006%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 23168001, 29202755, 29773157, 30059973). ClinVar contains an entry for this variant (Variation ID: 574312). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiac arrhythmia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 22, 2023	This missense variant replaces arginine with cysteine at codon 1023 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with ventricular fibrillation and structural myocardial alteration (PMID: 23168001), Brugada syndrome (PMID: 29202755), alcohol-induced cardiomyopathy (ACM) (PMID: 29773157), and tetralogy of Fallot (PMID: 22407026, 29121719 ). This variant has also been reported in 6 individuals suspected of having epilepsy, and in 3 individuals affected with other diseases other than inherited arrhythmia (PMID: 31696929). This variant has been identified in 5/247718 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces arginine with cysteine at codon 1023 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with ventricular fibrillation and structural myocardial alteration (PMID: 23168001), Brugada syndrome (PMID: 29202755), alcohol-induced cardiomyopathy (ACM) (PMID: 29773157), and tetralogy of Fallot (PMID: 22407026, 29121719 ). This variant has also been reported in 6 individuals suspected of having epilepsy, and in 3 individuals affected with other diseases other than inherited arrhythmia (PMID: 31696929). This variant has been identified in 5/247718 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 23, 2019

Variant summary: SCN5A c.3067C>T (p.Arg1023Cys) results in a non-conservative amino acid change located in the Sodium ion transport-associated domain (IPR010526) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 247718 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3067C>T has been reported in the literature in individuals affected with Cardiomyopathy including Tetralogy of Fallot, Brugada syndrome, ventricular fibrillation (e.g. Chiu_2012, Chiu_2017, Hayano_2014, Matsumura_2017, Watanabe_2013). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2023

The p.R1023C variant (also known as c.3067C>T), located in coding exon 16 of the SCN5A gene, results from a C to T substitution at nucleotide position 3067. The arginine at codon 1023 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the DII/DIII interdomain linker region. This variant has been detected in an individual with ventricular fibrillation, and early repolarization as well as cardiomyocyte disarray and fibrosis, and has also been detected in a Brugada syndrome cohort; however, clinical details were limited (Watanabe H et al. Int. J. Cardiol., 2013 May;165:e21-3; Matsumura H et al. J. Biomed. Sci., 2017 Dec;24:91). This alteration has also been reported in arrhythmia cohorts, in a cohort of subjects with tetralogy of Fallot and ventricular fibrillation, cardiomyopathy, epilepsy and control cohorts (Chiu SN et al. Int J Cardiol, 2017 Dec;249:156-160; Baruteau AE et al. Eur Heart J, 2018 Aug;39:2879-2887; Ware JS et al. J Am Coll Cardiol, 2018 May;71:2293-2302; Li X et al. Ann Hum Genet, 2020 Mar;84:161-168; Sarica AS et al. Am J Cardiol, 2021 Jul;151:51-56; (Kars ME et al. Proc Natl Acad Sci U S A, 2021 Sep;118:). This alteration was also reported along with an alteration in VCP in a one month old with amyotrophy, inclusion body myopathy with early onset Paget disease and frontotemporal dementia (Liu J et al. Hum Mutat, 2021 Nov;42:1443-1460). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

CardioboostArm

Benign

0.00062

CardioboostCm

Benign

0.0015

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Uncertain

-0.020

Cadd

Uncertain

Dann

Pathogenic

1.0

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.83

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.89

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

MetaSVM

Uncertain

0.086

MutationTaster

Benign

0.98

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

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.31

N;N;N;N;N;N;N;N;N

REVEL

Pathogenic

0.81

Sift

Benign

0.17

T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.065

T;T;T;T;T;T;T;T;T

Polyphen

0.0040

B;D;.;B;.;D;D;.;.

Vest4

0.77

MutPred

0.74

Loss of solvent accessibility (P = 0.1744);Loss of solvent accessibility (P = 0.1744);Loss of solvent accessibility (P = 0.1744);Loss of solvent accessibility (P = 0.1744);Loss of solvent accessibility (P = 0.1744);Loss of solvent accessibility (P = 0.1744);Loss of solvent accessibility (P = 0.1744);Loss of solvent accessibility (P = 0.1744);Loss of solvent accessibility (P = 0.1744);

MVP

0.57

MPC

0.24

ClinPred

0.46

GERP RS

5.3

Varity_R

0.060

gMVP

0.65

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