3-38581091-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM1PP2BP4_StrongBS1BS2

The NM_000335.5(SCN5A):c.3068G>A(p.Arg1023His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,604,920 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 3 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7O:1

Conservation

PhyloP100: 1.30

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 Benign. Variant got -9 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 267) in uniprot entity SCN5A_HUMAN there are 26 pathogenic changes around while only 11 benign (70%) in NM_000335.5

PP2

Missense variant in the SCN5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. Gene score misZ: 2.7504 (below the threshold of 3.09). Trascript score misZ: 4.8279 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.038592875).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000139 (21/150800) while in subpopulation SAS AF= 0.0017 (8/4696). AF 95% confidence interval is 0.000847. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.3068G>A	p.Arg1023His	missense_variant	Exon 17 of 28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.3068G>A	p.Arg1023His	missense_variant	Exon 17 of 28	ENST00000423572.7	NP_000326.2	Q14524-2Q86V90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 link	c.3068G>A	p.Arg1023His	missense_variant	Exon 17 of 28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.3068G>A	p.Arg1023His	missense_variant	Exon 17 of 28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.000139

AC:

AN:

150684

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000658

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00170

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000283

AC:

AN:

247778

Hom.:

AF XY:

0.000431

AC XY:

AN XY:

134592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00186

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000536

Gnomad OTH exome

AF:

0.000497

GnomAD4 exome

AF:

0.000174

AC:

253

AN:

1454120

Hom.:

Cov.:

AF XY:

0.000235

AC XY:

170

AN XY:

723272

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.00229

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000280

Gnomad4 OTH exome

AF:

0.000150

GnomAD4 genome

AF:

0.000139

AC:

AN:

150800

Hom.:

Cov.:

AF XY:

0.000217

AC XY:

AN XY:

73696

show subpopulations

Gnomad4 AFR

AF:

0.0000243

Gnomad4 AMR

AF:

0.000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00170

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000425

Hom.:

Bravo

AF:

0.000178

ExAC

AF:

0.000347

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

May 28, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SCN5A c.3068G>A; p.Arg1023His variant (rs199473592) is reported in the literature in an individual affected with Brugada syndrome (Frustaci 2005). This variant was also reported in an individual affected with long QT syndrome; however, this individual also carried a frameshift variant in a different gene that likely explained their phenotype (Fernandes 2015). The p.Arg1023His variant is found in the South Asian population with an overall allele frequency of 0.19% (57/30564 alleles) in the Genome Aggregation Database. The arginine at codon 1023 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Another amino acid substitution at this codon (p.Arg1023Cys) has been reported in individuals with Brugada syndrome or ventricular arrhythmia, but its clinical significance has not been conclusively demonstrated (Matsumura 2017, Watanabe 2013). Functional studies of the p.Arg1023His variant provide conflicting results. One study reported a lower peak current density and longer time of inactivation (Frustaci 2005), while a second study found normal peak current density in cells expressing p.Arg1023His alone and greater peak current density when expressed together with wildtype SCN5A (Hoshi 2014). Due to conflicting information, the clinical significance of the p.Arg1023His variant is uncertain at this time. References: Fernandes M et al. Long QT syndrome with mutations in three genes: A rare case. Rev Port Cardiol. 2015;34(5):359.e1-359.e3595. Frustaci A et al. Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome. Circulation. 2005 Dec 13;112(24):3680-7. Hoshi M et al. Brugada syndrome disease phenotype explained in apparently benign sodium channel mutations. Circ Cardiovasc Genet. 2014 Apr;7(2):123-31. Matsumura H et al. H558R, a common SCN5A polymorphism, modifies the clinical phenotype of Brugada syndrome by modulating DNA methylation of SCN5A promoters. J Biomed Sci. 2017;24(1):91. Watanabe H et al. SCN5A mutation associated with ventricular fibrillation, early repolarization, and concealed myocardial abnormalities. Int J Cardiol. 2013;165(2):e21-e23. -

May 29, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16344400, 24573164, 17512504, 25935074, 23168001, 29728395, 27560382, 30662450, 33131149) -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1Benign:1

Aug 12, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 Brugada proband; also 1 paper reporting functional impact; However, frequency high for disorder; ClinVar: P by GeneDx -

Jan 28, 2019

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN5A c.3068G>A (p.Arg1023His) results in a non-conservative amino acid change located in the Sodium ion transport-associated domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 275816 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), suggesting that the variant may be benign. c.3068G>A has been reported in the literature in at least one individual affected with Arrhythmia (Frustaci_2005). This report does not provide unequivocal conclusions about association of the variant with Arrhythmia. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity as measured by voltage gated sodium current density (Frustaci_2005, Hoshi_2014). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, one of whom have classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Brugada syndrome 1

Benign:1

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy

Benign:1

Mar 30, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Feb 04, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cardiac arrhythmia

Benign:1

Nov 11, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brugada syndrome

Other:1

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Brugada syndrome in the following publications (PMID:16344400). 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

Benign

0.10

CardioboostCm

Benign

0.0011

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.51

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

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.87

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

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.039

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

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.78

.;N;.;.;.;N;.;.;.

PrimateAI

Benign

0.27

PROVEAN

Benign

0.56

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

REVEL

Uncertain

0.47

Sift

Benign

0.51

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

Sift4G

Benign

0.16

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

Polyphen

0.0040

B;B;.;B;.;B;B;.;.

Vest4

0.11

MutPred

0.82

Gain of glycosylation at K1024 (P = 0.1429);Gain of glycosylation at K1024 (P = 0.1429);Gain of glycosylation at K1024 (P = 0.1429);Gain of glycosylation at K1024 (P = 0.1429);Gain of glycosylation at K1024 (P = 0.1429);Gain of glycosylation at K1024 (P = 0.1429);Gain of glycosylation at K1024 (P = 0.1429);Gain of glycosylation at K1024 (P = 0.1429);Gain of glycosylation at K1024 (P = 0.1429);

MVP

0.96

MPC

0.037

ClinPred

0.016

GERP RS

2.5

Varity_R

0.043

gMVP

0.49

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