rs199473552

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

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

Scores

1
20

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3O:1

Conservation

PhyloP100: 0.520

Publications

12 publications found
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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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
SCN5ANM_001099404.2 linkc.103G>A p.Gly35Ser missense_variant Exon 2 of 28 ENST00000413689.6 NP_001092874.1 Q14524H9KVD2
SCN5ANM_000335.5 linkc.103G>A p.Gly35Ser missense_variant Exon 2 of 28 ENST00000423572.7 NP_000326.2 Q14524-2Q86V90

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN5AENST00000413689.6 linkc.103G>A p.Gly35Ser missense_variant Exon 2 of 28 5 NM_001099404.2 ENSP00000410257.1 H9KVD2
SCN5AENST00000423572.7 linkc.103G>A p.Gly35Ser missense_variant Exon 2 of 28 1 NM_000335.5 ENSP00000398266.2 Q14524-2

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152058
Hom.:
0
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
8
15
23
30
38
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152058
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74262
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
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:5Benign:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign: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:1Other: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

Publications

Other links and lift over

dbSNP: rs199473552; hg19: chr3-38674696; COSMIC: COSV60067103; API