rs199473552

Variant names:

• chr3-38633205-C-T
• rs199473552
• NM_001099404.2:c.103G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001099404.2(SCN5A):​c.103G>A​(p.Gly35Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000855 in 1,613,254 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/24 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. G35C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000091 (1 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3 O:1
• Conservation: PhyloP100: 0.520
• Publications: 12 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13819748).
• BP6: Variant 3-38633205-C-T is Benign according to our data. Variant chr3-38633205-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67628. Variant chr3-38633205-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67628. Variant chr3-38633205-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67628. Variant chr3-38633205-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67628. Variant chr3-38633205-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67628. Variant chr3-38633205-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67628. Variant chr3-38633205-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67628. Variant chr3-38633205-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67628. Variant chr3-38633205-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67628. Variant chr3-38633205-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67628. Variant chr3-38633205-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67628. Variant chr3-38633205-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67628. Variant chr3-38633205-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67628. Variant chr3-38633205-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67628. Variant chr3-38633205-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67628. Variant chr3-38633205-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67628. Variant chr3-38633205-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67628. Variant chr3-38633205-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67628. Variant chr3-38633205-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 67628.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.103G>A	p.Gly35Ser	missense_variant	Exon 2 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.103G>A	p.Gly35Ser	missense_variant	Exon 2 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.103G>A	p.Gly35Ser	missense_variant	Exon 2 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.103G>A	p.Gly35Ser	missense_variant	Exon 2 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152058 Hom.: 0 Cov.: 32

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000966 AC: 24 AN: 248566 AF XY: 0.000126

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000910 AC: 133 AN: 1461196 Hom.: 1 Cov.: 31 AF XY: 0.000103 AC XY: 75 AN XY: 726902

African (AFR) AF: 0.000149 AC: 5 AN: 33476

American (AMR) AF: 0.0000447 AC: 2 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53098

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5680

European-Non Finnish (NFE) AF: 0.000106 AC: 118 AN: 1111824

Other (OTH) AF: 0.0000829 AC: 5 AN: 60348

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74262

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000107 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000141 AC: 17

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Aug 06, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 67628; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 33131149, 29728395, 23414114, 25904541, 20877689, 18752142, 11960580, 23805106) -

Apr 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SCN5A c.103G>A; p.Gly35Ser variant (rs199473552; ClinVar Variation ID: 67628) is reported in the literature in several individuals affected with Brugada syndrome or long QT syndrome (Berge 2008, Levy-Nissenbaum 2001). This variant is found in the non-Finnish European population with an allele frequency of 0.02% (22/128076 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.212). Functional studies of the variant protein suggest it has similar electrophysiological properties to wildtype SCN5A (Gutter 2013). However, due to limited information, the clinical significance of the p.Gly35Ser variant is uncertain at this time. References: Berge et al. Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers. Scand J Clin Lab Invest. 2008;68(5):362-8. PMID: 18752142. Gutter et al. Characterization of N-terminally mutated cardiac Na(+) channels associated with long QT syndrome 3 and Brugada syndrome. Front Physiol. 2013 Jun 26;4:153. PMID: 23805106. Levy-Nissenbaum et al. Genetic analysis of Brugada syndrome in Israel: two novel mutations and possible genetic heterogeneity. Genet Test. 2001 Winter;5(4):331-4. PMID: 11960580. -

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brugada syndrome Uncertain:1 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:11960580;PMID:18752142). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Oct 07, 2015

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SCN5A-related disorder Uncertain:1

Sep 01, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiovascular phenotype Uncertain:1

Sep 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.103G>A (p.G35S) alteration is located in exon 2 (coding exon 1) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 103, causing the glycine (G) at amino acid position 35 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Aug 08, 2022

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.103G>A (p.Gly35Ser) results in a non-conservative amino acid change in 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 9.7e-05 in 248566 control chromosomes, predominantly at a frequency of 0.00018 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no penetrant association of c.103G>A in individuals affected with Brugada syndrome/Arrhythmia/SCN5A-related disorders have been reported. A recently published systematic literature review evaluating 561 SCN5A variants associated with Brugada syndrome reported this variant among a subset that were classified with an ACMG score of benign based on lack of impact on channel function (example, Pearman_2020). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiac arrhythmia Benign:1

May 24, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
CardioboostArm	Benign	0.0000024
CardioboostCm	Benign	0.0015
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	6.5
DANN	Benign	0.85
DEOGEN2	Benign	0.35	.;.;.;.;.;T;.;.;.;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.81	.;T;T;T;T;T;T;.;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.090	.;N;.;.;.;N;.;.;.;.;.
PhyloP100		0.52
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.89	N;N;N;N;N;N;N;N;N;.;N
REVEL	Benign	0.21
Sift	Benign	0.18	T;T;T;T;T;T;T;T;T;.;T
Sift4G	Benign	0.32	T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.0010	B;B;.;B;.;B;B;.;.;.;.
Vest4		0.14
MVP		0.70
MPC		0.36
ClinPred		0.044	T
GERP RS		-0.15
PromoterAI		0.0092	Neutral
Varity_R		0.035
gMVP		0.43
Mutation Taster		=32/68	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: rs199473552; hg19: chr3-38674696; COSMIC: COSV60067103;