chr3-38606007-C-T

Position:

chr3-38606007-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3

The NM_000335.5(SCN5A):c.1282G>A(p.Glu428Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:10O:1

Conservation

PhyloP100: 1.95

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 Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a helix (size 27) in uniprot entity SCN5A_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_000335.5

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.1282G>A	p.Glu428Lys	missense_variant	10/28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 linkuse as main transcript	c.1282G>A	p.Glu428Lys	missense_variant	10/28	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.1282G>A	p.Glu428Lys	missense_variant	10/28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 linkuse as main transcript	c.1282G>A	p.Glu428Lys	missense_variant	10/28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000482

AC:

AN:

248958

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

135024

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.0000655

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000709

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1461392

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

726936

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000486

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000947

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000239

AC:

ExAC

AF:

0.0000496

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 428 of the SCN5A protein (p.Glu428Lys). This variant is present in population databases (rs199473111, gnomAD 0.01%). This missense change has been observed in individuals with atrial fibrillation, Brugada syndrome, and/or long QT syndrome (PMID: 15996170, 18378609, 19026623, 24784157, 28341781, 29449639, 30193851, 33919104, 34019817). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30048). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 29449639, 34019817). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 08, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2022	Reported in association with atrial fibrillation, Brugada syndrome, LQTS, and sudden unexplained death (Darbar et al., 2008; Millat et al., 2009; Yamagata et al., 2017; Berthome et al., 2019; Hong et al., 2021; Iglesias et al., 2021; Ripoll-Vera et al., 2021); Reported in a family with LQTS in which the proband harbored three clinically relevant variants, however, the SCN5A variant did not independently segregate with disease in family members (Wu et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies have demonstrated conflicting evidence regarding impact on electrophysiological properties and protein function (Wu et al., 2018; Hong et al., 2021; Ishikawa et al., 2021); LQTS is caused by gain of function variants in the SCN5A channel (NaV1.5), while Brugada syndrome is caused by loss of function variants; as this variant has been identified in individuals with diseases that have different mechanisms of pathogenicity, its clinical significance is uncertain; This variant is associated with the following publications: (PMID: 22581653, 19026623, 24055113, 24784157, 25637381, 21596231, 15996170, 28341781, 29449639, 34219138, 34019817, 30193851, 18378609, 33919104, 32917565, 34831398) -

Cardiac arrhythmia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 03, 2024	This missense variant replaces glutamic acid with lysine at codon 428 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant causes increased peak sodium current but has no effect on late channel current in vitro (PMID: 29449639, 34019817). This variant has also been shown to cause abnormal electrophysiological profiles in cardiomyocytes derived from induced pluripotent stem cells from Glu428Lys carriers who were affected with atrial fibrillation (PMID: 34019817). This variant has been reported in two individuals affected with long QT syndrome (PMID: 19026623, 29449639), one individual affected with Brugada syndrome (PMID: 28341781), two individuals affected with sudden cardiac death (PMID: 32917565, 33919104, 37432518), as well as in three related individuals who were asymptomatic with no QT prolongation (PMID: 29449639). One of these affected individuals also carried two pathogenic variants in other genes that could explain the observed phenotype (PMID: 29449639). This variant has been shown to segregate with atrial fibrillation in three individuals from a family (PMID 18378609, 34019817). This variant has been identified in 14/280354 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	Dec 01, 2023	This missense variant replaces glutamic acid with lysine at codon 428 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant causes increased peak sodium current but has no effect on late channel current in vitro (PMID: 29449639, 34019817). This variant has also been shown to cause abnormal electrophysiological profiles in cardiomyocytes derived from induced pluripotent stem cells from Glu428Lys carriers who were affected with atrial fibrillation (PMID: 34019817). This variant has been reported in two individuals affected with long QT syndrome (PMID: 19026623, 29449639), one individual affected with Brugada syndrome (PMID: 28341781), two individuals affected with sudden cardiac death (PMID: 32917565, 33919104, 37432518), as well as in three related individuals who were asymptomatic with no QT prolongation (PMID: 29449639). One of these affected individuals also carried two pathogenic variants in other genes that could explain the observed phenotype (PMID: 29449639). This variant has been shown to segregate with atrial fibrillation in three individuals from a family (PMID 18378609, 34019817). This variant has been identified in 14/280354 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. -

Atrial fibrillation

Uncertain:1Other:1

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
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. -

Atrial fibrillation, familial, 10

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 15, 2008

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 05, 2024

Variant summary: SCN5A c.1282G>A (p.Glu428Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 248958 control chromosomes (gnomAD v2.1). The observed variant frequency is approximately 1.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Atrial Fibrillation phenotype (3.1e-05), suggesting that the variant might be benign. On the other hand, the variant c.1282G>A has been reported in the literature in individuals affected with atrial fibrillation (AF; Darbar_2008, Hong_2021), long QT syndrome (LQTS; Millat_2009, Wu_2018), Brugada syndrome (BrS; Yamagata_2017, Berthome _2019), sudden unexplained death (SUD; Ripoll-Vera_2021, Iglesias_2021, Hata_2023), but was also found healthy controls or was reported as an incidental finding in patients undergoing genetic testing for other reasons (e.g. Maekawa_2005, Lawrence_2014, Weeke_2015, Amendola_2015, Kapplinger_2015). Of note, in a family affected with AF, the variant seemed to segregate with the phenotype (Darbar_2008, Hong_2021), while in another family affected with LQTS, two co-occurring pathogenic variants in other genes could explain the phenotype (Wu_2018). Multiple publications reported experimental evidence evaluating an impact on protein function, and demonstrated in induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) isolated from patients that the variant was associated with spontaneous arrhythmogenic activity (with beat-to-beat irregularity, prolonged action potential duration) and transcriptomic analyses suggested that the nitric oxide (NO) signaling pathway modulated late sodium currents (Hong_2021, Brown_2024). While other studies reported conflicting results, demonstrating decreased- or increased peak Na current in in vitro expression systems (Ishikawa_2021, Wu_2018). The following publications have been ascertained in the context of this evaluation (PMID: 18378609, 34019817, 38241367, 34219138, 19026623, 29449639, 28341781, 30193851, 33919104, 32917565, 37432518, 15996170, 24784157, 25410959, 25637381, 25904541). ClinVar contains an entry for this variant (Variation ID: 30048). Based on the evidence outlined above, the variant was classified as uncertain significance. -

SCN5A-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2024

The SCN5A c.1282G>A variant is predicted to result in the amino acid substitution p.Glu428Lys. This variant has been reported in individuals with atrial fibrillation, Brugada syndrome, sudden cardiac death, or long QT syndrome (Table 2, Darbar et al. 2008. PubMed ID: 18378609; Yamagata et al. 2017. PubMed ID: 28341781; Iglesias et al. 2021. PubMed ID: 33919104; Hata et al. 2023. PubMedID: 37432518; Wu et al. 2018. PubMed ID: 29449639). However, variants in additional genes were also reported in some of these patients (Iglesias et al. 2021. PubMed ID: 33919104; Hata et al. 2023. PubMedID: 37432518). This variant was also reported in a family with long QT syndrome and syncope along with two variants in relevant genes; however the p.Glu428Lys variant did not segregate with disease (Wu et al. 2018. PubMed ID: 29449639). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD. The results of in vitro experimental studies of this variant are inconclusive (Table S4, Ishikawa et al. 2021. PubMed ID: 34219138; Figure 4, Hong et al. 2021. PubMed ID: 34019817). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Mar 28, 2022

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2023

The p.E428K variant (also known as c.1282G>A), located in coding exon 9 of the SCN5A gene, results from a G to A substitution at nucleotide position 1282. The glutamic acid at codon 428 is replaced by lysine, an amino acid with similar properties. This variant has been detected in three individuals in a family with atrial fibrillation (Darbar D et al. Circulation. 2008;117:1927-35). This variant has also been detected in long QT syndrome (LQTS) and Brugada syndrome cohorts; however, clinical details were limited (Millat G et al. Clin Biochem. 2009;42(6):491-9; Yamagata K et al. Circulation. 2017;135:2255-2270). In one family with LQTS, this variant co-occurred with alterations in KCNH2 and KCNQ1. The p.E428K variant and the KCNQ1 variant were inherited from the proband's maternal side which had no history of LQTS. The same study reported in vitro assay results that suggested this variant may have some impact on channel function (Wu J et al. Sci Rep. 2018;8(1):3129). This variant has also been detected in multipe individuals from exome sequencing cohorts and arrhythmia control cohorts (Maekawa K et al. Ann Hum Genet. 2005;69(Pt 4):413-28; Lawrence L et al. Genet. Med. 2014;16:741-50; Weeke P et al. Circ Cardiovasc Genet. 2015;8(1):58-63; Amendola LM et al. Genome Res. 2015;25:305-15; Kapplinger JD et al. Circ Cardiovasc Genet. 2015;8:582-95). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

0.069

CardioboostCm

Benign

0.076

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

.;.;.;.;.;D;.;.;.

Eigen

Benign

-0.041

Eigen_PC

Benign

0.078

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.94

.;D;D;D;D;D;D;.;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.79

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Benign

1.0

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

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.1

D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.66

Sift

Benign

0.085

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

Sift4G

Benign

0.37

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

Polyphen

0.041

B;D;.;B;.;B;P;.;.

Vest4

0.85

MVP

0.91

MPC

0.78

ClinPred

0.22

GERP RS

4.7

Varity_R

0.13

gMVP

0.83

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

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