rs199473197

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 7P and 2B. PM1PM2PM5PP2BP4_Moderate

The NM_000335.5(SCN5A):c.3389C>T(p.Thr1130Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,608,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. T1130N) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense, splice_region

Scores

Splicing: ADA: 0.00003185

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8O:1

Conservation

PhyloP100: -0.191

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 links:

SCN5A (HGNC:):

SCN5A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 267) in uniprot entity SCN5A_HUMAN there are 26 pathogenic changes around while only 11 benign (70%) in NM_000335.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-38576780-G-T is described in Lovd as [Likely_pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ 2.7504 (greater than the threshold 3.09). Trascript score misZ 4.8279 (greater than threshold 3.09). GenCC has associacion of gene with progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.096125245).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.3392C>T	p.Thr1131Ile	missense_variant, splice_region_variant	19/28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 linkuse as main transcript	c.3389C>T	p.Thr1130Ile	missense_variant, splice_region_variant	19/28	ENST00000423572.7	NP_000326.2	Q14524-2Q86V90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.3392C>T	p.Thr1131Ile	missense_variant, splice_region_variant	19/28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 linkuse as main transcript	c.3389C>T	p.Thr1130Ile	missense_variant, splice_region_variant	19/28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000919

AC:

AN:

152266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000313

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000251

AC:

AN:

238604

Hom.:

AF XY:

0.0000155

AC XY:

AN XY:

129300

show subpopulations

Gnomad AFR exome

AF:

0.000208

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000173

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000824

AC:

AN:

1455944

Hom.:

Cov.:

AF XY:

0.00000967

AC XY:

AN XY:

723520

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000758

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152384

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74524

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000121

ESP6500AA

AF:

0.000237

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 02, 2017	Variant summary: The c.3392C>T (p.Thr1131Ile) in SCN5A gene is a missense change that involves a non-conserved nucleotide resulting in a non-conservative amino acid substitution located within the cytoplasmic loop between domains II-III. 4/5 in silico tools predict benign, although at least one functional study have shown deleterious effect on the protein function, suggesting a potential causative reason for atrial fibrillation (AF) (Wang, 2010). However, this study has yet to be published in peer-reviewed journal at this time of this review therefore the evidence cannot be unequivocally considered. The variant is present in the large control population dataset of ExAC at a frequency of 4.455e-05 (4/89792 chrs tested), predominantly in individuals of African descent (0.000417; 3/7194 chrs tested). The variant has also been identified in gnomAD dataset at similar frequencies (0.00003; 8/267102 chrs tested). The observed frequency in African cohort exceeds the maximal expected frequency of a pathogenic allele (0.00016) in this gene. However, since no clinical information on ExAC participants are available, the possibility of them being a silent carrier of deleterious variant cannot be ruled out. In addition, the variant was reported in two patients presented with AF and SIDS. Both cases were reported to be of African descent. Since no segregation analysis was done for these patients, there are not enough evidence to classify this variant with confidence. Lastly, the c.3392C>T is cites as VUS by several reputable databases/clinical laboratories. Taking all line of evidence into consideration, the variant was classified as VUS until more information becomes available. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 28, 2023	The SCN5A c.3392C>T; p.Thr1131Ile variant (rs199473197) is reported in an individual with atrial fibrillation (Darbar 2008) and in a cohort of sudden unexplained deaths (Lin 2017). This variant is also reported in ClinVar (Variation ID: 67795). It is found on eight alleles in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.345). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Darbar D et al. Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation. Circulation. 2008 Apr 15;117(15):1927-35. PMID: 18378609. Lin Y et al. Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths. Circ Cardiovasc Genet. 2017 Dec;10(6):e001839. PMID: 29247119. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2019	Identified in individuals referred for cardiac genetic testing at GeneDx; however, at least one of these probands harbored a pathogenic variant in another cardiac disease-related gene; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 67795; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29247119, 18378609, 21143119, 25175087, 24631775, 28316956, 25904541) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1131 of the SCN5A protein (p.Thr1131Ile). This variant is present in population databases (rs199473197, gnomAD 0.02%). This missense change has been observed in individual(s) with atrial fibrillation (PMID: 18378609, 24631775). ClinVar contains an entry for this variant (Variation ID: 67795). 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

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 06, 2022	This missense variant replaces threonine with isoleucine at codon 1131 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). An in vitro functional study has shown that this variant affects the voltage-dependence of channel activation (Wang et al., 2010). This variant has been reported in an individual affected with atrial fibrillation (AF) who has a family history of AF, with both parents and two children affected (PMID: 18378609), and in another individual with sudden unexplained death (PMID: 24631775). This variant has been identified in 8/270004 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 17, 2024	This missense variant replaces threonine with isoleucine at codon 1131 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). An in vitro functional study has shown that this variant affects the voltage-dependence of channel activation (Wang et al., 2010). This variant has been reported in an individual affected with atrial fibrillation (AF), who has a family history of AF, with both parents and two children affected (PMID: 18378609). This variant has also been found in an individual with sudden unexplained death (PMID: 24631775), and in another individual who experienced sudden cardiac arrest and was affected with mitral valve prolapse and prolonged QTc (PMID: 34317510). This variant has been identified in 8/270004 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. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 22, 2021

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2023

The p.T1131I variant (also known as c.3392C>T), located in coding exon 18 of the SCN5A gene, results from a C to T substitution at nucleotide position 3392. The threonine at codon 1131 is replaced by isoleucine, an amino acid with similar properties, and is located in the DII/DIII interdomain linker region of the protein. This variant has been detected in an individual with atrial fibrillation, bradycardia, and congestive heart failure, and has been detected in a sudden infant death case (Darbar D et al. Circulation, 2008 Apr;117:1927-35; Wang D et al. Forensic Sci. Int., 2014 Apr;237:90-9). This variant has also been detected in a control cohort; however, details were limited (Kapplinger JD et al. Circ Cardiovasc Genet. 2015 Aug;8(4):582-95). This amino acid position is not 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. -

Atrial fibrillation

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 Atrial fibrillation in the following publications (PMID:18378609). 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

0.074

CardioboostCm

Benign

0.0045

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.12

CADD

Benign

8.0

DANN

Benign

0.86

DEOGEN2

Benign

0.38

.;.;.;.;.;T;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.57

.;T;T;T;T;T;T;.;T

M_CAP

Uncertain

0.29

MetaRNN

Benign

0.096

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

0.90

.;.;.;.;.;L;.;.;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.28

N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.34

Sift

Benign

0.19

T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.20

T;T;T;T;T;T;T;T;T

Polyphen

0.0060

B;B;.;B;.;B;B;.;.

Vest4

0.22

MVP

0.68

MPC

0.032

ClinPred

0.018

GERP RS

0.16

Varity_R

0.034

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000032

dbscSNV1_RF

Benign

0.0060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over