NM_001099404.2:c.280A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001099404.2(SCN5A):​c.280A>G​(p.Ile94Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000734 in 1,608,172 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I94S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

7
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 2.81

Publications

5 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 -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.20385548).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN5ANM_001099404.2 linkc.280A>G p.Ile94Val missense_variant Exon 3 of 28 ENST00000413689.6 NP_001092874.1 Q14524H9KVD2
SCN5ANM_000335.5 linkc.280A>G p.Ile94Val missense_variant Exon 3 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.280A>G p.Ile94Val missense_variant Exon 3 of 28 5 NM_001099404.2 ENSP00000410257.1 H9KVD2
SCN5AENST00000423572.7 linkc.280A>G p.Ile94Val missense_variant Exon 3 of 28 1 NM_000335.5 ENSP00000398266.2 Q14524-2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152154
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000120
AC:
3
AN:
249412
AF XY:
0.0000148
show subpopulations
Gnomad AFR exome
AF:
0.0000645
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000884
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000790
AC:
115
AN:
1456018
Hom.:
0
Cov.:
28
AF XY:
0.0000607
AC XY:
44
AN XY:
724782
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33354
American (AMR)
AF:
0.00
AC:
0
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26096
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39672
South Asian (SAS)
AF:
0.0000232
AC:
2
AN:
86132
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53404
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
0.000100
AC:
111
AN:
1106684
Other (OTH)
AF:
0.0000332
AC:
2
AN:
60198
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.506
Heterozygous variant carriers
0
6
12
17
23
29
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
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:
0.0000197
AC:
3
AN:
152154
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74314
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41442
American (AMR)
AF:
0.00
AC:
0
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5180
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000441
AC:
3
AN:
68022
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.442
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:
0.0000609
Hom.:
0
ESP6500AA
AF:
0.000235
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Feb 03, 2020
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25904541, 24613995) -

Jan 01, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 94 of the SCN5A protein (p.Ile94Val). This variant is present in population databases (rs202114798, gnomAD 0.007%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 24613995, 33500567, 34930020, 37652022). ClinVar contains an entry for this variant (Variation ID: 463314). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiac arrhythmia Uncertain:2
Sep 23, 2024
All of Us Research Program, National Institutes of Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces isoleucine with valine at codon 94 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant causes a reduction of channel activity in cell culture (PMID: 24613995), while another in vitro study reported this variant does not change channel function (PMID: 34930020). This variant has been reported in an individual affected with irritable bowel syndrome who showed an Brugada-type ECG (PMID: 24613995), in an individual affected with left ventricular noncompaction (PMID: 33500567), and in three individuals affected with atrial fibrillation, long QT syndrome, and/or premature ventricular contraction (PMID: 34930020). This variant has been identified in 3/249412 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jun 03, 2024
Color Diagnostics, LLC DBA Color Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces isoleucine with valine at codon 94 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant causes a reduction of channel activity in cell culture (PMID: 24613995), while another in vitro study reported this variant does not change channel function (PMID: 34930020). This variant has been reported in an individual affected with irritable bowel syndrome who showed an Brugada-type ECG (PMID: 24613995), in an individual affected with left ventricular noncompaction (PMID: 33500567), and in three individuals affected with atrial fibrillation, long QT syndrome, and/or premature ventricular contraction (PMID: 34930020). This variant has been identified in 3/249412 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:1
Jul 28, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.Ile94Val variant in SCN5A has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/9808 African chromosomes and 1 /16508 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs202114798). Computational prediction tools and conservation analysis suggest that the p.Ile94Val variant may not impact the pr otein, though this information is not predictive enough to rule out pathogenicit y. Of note, a different variant at this amino acid position (p.Ile94Ser) has bee n identified in 1 individual with Brugada Syndrome (Kapplinger 2010). In summary , the clinical significance of the p.Ile94Val variant is uncertain. -

SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Uncertain:1
Oct 16, 2021
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Long QT syndrome 3 Uncertain:1
Sep 22, 2024
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome 1 (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome 3 (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss of function or gain of function mechanism (PMID: 29798782). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited; however, SSS is caused by biallelic variants (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 20301690). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS by multiple clinical laboratories in ClinVar, and has been observed in individuals with dilated cardiomyopathy, long QT syndrome or irritable bowel syndrome (PMID: 34930020, 31983221, 24613995). (I) 1010 - Functional evidence for this variant is inconclusive. Patch clamp studies showed that this variant displayed similar properties to wild type on most measures except for a decrease in slope of the voltage dependence of inactivation (PMID: 24613995). (I) 1206 - This variant has been shown to be paternally inherited (by Sanger analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cardiovascular phenotype Uncertain:1
Jul 09, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.I94V variant (also known as c.280A>G), located in coding exon 2 of the SCN5A gene, results from an A to G substitution at nucleotide position 280. The isoleucine at codon 94 is replaced by valine, an amino acid with highly similar properties, and is located in the N-terminal, cytoplasmic region. This variant was detected in an individual from an irritable bowel syndrome cohort who was reported to have Brugada syndrome pattern on ECG, and in individuals with electronic health record indication of arrhythmia (Beyder A. Gastroenterology. 2014;146(7):1659-1668; Glazer AM et al. Circulation. 2022 03;145(12):877-891). This variant has also been detected in an individual from a control cohort (Kapplinger JD. Circ Cardiovasc Genet. 2015 Aug;8(4):582-95). In vitro studies reported this variant to have peak current density similar to wild type, but some impact to other parameters of channel function (Beyder A. Gastroenterology. 2014;146(7):1659-1668; Glazer AM et al. Circulation. 2022 03;145(12):877-891). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
CardioboostArm
Benign
9.7e-7
CardioboostCm
Benign
0.0059
BayesDel_addAF
Benign
-0.013
T
BayesDel_noAF
Uncertain
-0.070
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.39
.;.;.;.;.;T;.;.;.;T
Eigen
Benign
-0.17
Eigen_PC
Benign
0.022
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.87
.;D;D;D;D;D;D;.;D;D
M_CAP
Benign
0.055
D
MetaRNN
Benign
0.20
T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.35
D
MutationAssessor
Benign
0.97
.;L;.;.;.;L;.;.;.;.
PhyloP100
2.8
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-0.56
N;N;N;N;N;N;N;N;N;.
REVEL
Uncertain
0.31
Sift
Benign
0.26
T;T;T;T;T;T;T;T;T;.
Sift4G
Benign
0.50
T;T;T;T;T;T;T;T;T;T
Polyphen
0.0090
B;B;.;B;.;B;B;.;.;.
Vest4
0.35
MVP
0.53
MPC
0.48
ClinPred
0.36
T
GERP RS
5.1
Varity_R
0.10
gMVP
0.54
Mutation Taster
=13/87
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: rs202114798; hg19: chr3-38671914; API