3-38581091-C-T

Variant names:

• chr3-38581091-C-T
• rs199473592
• NM_001099404.2:c.3068G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001099404.2(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. 14/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1023L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (3 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7 O:1
• Conservation: PhyloP100: 1.30
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• Brugada syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Brugada syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1E

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• sick sinus syndrome 1

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial heart block, type 1A

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• atrial standstill

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sick sinus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal familial ventricular fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038592875).
• BP6: Variant 3-38581091-C-T is Benign according to our data. Variant chr3-38581091-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67775.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 SD,AD,AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000139 AC: 21 AN: 150684 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000283 AC: 70 AN: 247778 AF XY: 0.000431

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 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.: 3 Cov.: 37 AF XY: 0.000235 AC XY: 170 AN XY: 723272

African (AFR) AF: 0.000120 AC: 4 AN: 33316

American (AMR) AF: 0.000157 AC: 7 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25902

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39280

South Asian (SAS) AF: 0.00229 AC: 197 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51442

Middle Eastern (MID) AF: 0.000697 AC: 4 AN: 5736

European-Non Finnish (NFE) AF: 0.0000280 AC: 31 AN: 1107838

Other (OTH) AF: 0.000150 AC: 9 AN: 59886

GnomAD4 genome AF: 0.000139 AC: 21 AN: 150800 Hom.: 0 Cov.: 32 AF XY: 0.000217 AC XY: 16 AN XY: 73696

African (AFR) AF: 0.0000243 AC: 1 AN: 41100

American (AMR) AF: 0.000657 AC: 10 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5012

South Asian (SAS) AF: 0.00170 AC: 8 AN: 4696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67722

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.0000831 Hom.: 0

Bravo AF: 0.000178

ExAC AF: 0.000347 AC: 42

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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) -

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. -

not specified Uncertain:1 Benign:1

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. -

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 -

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
CardioboostArm	Benign	0.000064
CardioboostCm	Benign	0.0011
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	19
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	.;.;.;.;.;D;.;.;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.87	.;D;D;D;D;D;D;.;D
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.039	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.78	.;N;.;.;.;N;.;.;.
PhyloP100		1.3
PrimateAI	Benign	0.27	T
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	T
GERP RS		2.5
Varity_R		0.043
gMVP		0.49
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs199473592; hg19: chr3-38622582; COSMIC: COSV106104178;