3-38581091-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BP4_Strong

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. 14/23 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. R1023C) 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SCN5A
• BP4: Computational evidence support a benign effect (MetaRNN=0.038592875).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.3068G>A	p.Arg1023His	missense_variant	17/28	ENST00000413689.6
SCN5A	NM_000335.5	c.3068G>A	p.Arg1023His	missense_variant	17/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.3068G>A	p.Arg1023His	missense_variant	17/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.3068G>A	p.Arg1023His	missense_variant	17/28	1	NM_000335.5	A1

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

GnomAD3 exomes AF: 0.000283 AC: 70 AN: 247778 Hom.: 0 AF XY: 0.000431 AC XY: 58 AN XY: 134592

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

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

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.: 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

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 28, 2020	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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2019	This variant is associated with the following publications: (PMID: 16344400, 24573164, 17512504, 25935074, 23168001, 29728395, 27560382, 30662450, 33131149) -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 12, 2016	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 -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 28, 2019	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

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Mar 30, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 04, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 11, 2018

- -

Brugada 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 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
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.72	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
MutationTaster	Benign	0.91	N;N;N;N;N;N;N;N;N;N
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

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

Other links and lift over

dbSNP: rs199473592; hg19: chr3-38622582;