3-38633166-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001099404.2(SCN5A):c.142G>A(p.Glu48Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,613,180 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 (★★). Synonymous variant affecting the same amino acid position (i.e. E48E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9O:1

Conservation

PhyloP100: 1.68

Publications

8 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

SCN5A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.142G>A	p.Glu48Lys	missense_variant	Exon 2 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 link	c.142G>A	p.Glu48Lys	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 link	c.142G>A	p.Glu48Lys	missense_variant	Exon 2 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7 link	c.142G>A	p.Glu48Lys	missense_variant	Exon 2 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

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:

0.0000527

AC:

AN:

246818

AF XY:

0.0000820

show subpopulations

Gnomad AFR exome

AF:

0.000196

Gnomad AMR exome

AF:

0.0000582

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.0000269

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1461098

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

726814

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33474

American (AMR)

AF:

0.0000896

AC:

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.000101

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86158

European-Finnish (FIN)

AF:

0.0000751

AC:

AN:

53286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.0000342

AC:

AN:

1111682

Other (OTH)

AF:

0.00

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000460

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.0000966

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000850

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 48 of the SCN5A protein (p.Glu48Lys). This variant is present in population databases (rs199473048, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 19716085, 30086531, 31737537). ClinVar contains an entry for this variant (Variation ID: 67663). 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 does not substantially affect SCN5A function (PMID: 25904541). 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. -

Dec 11, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in association with LQTS, alcoholic cardiomyopathy, Brugada syndrome, and sudden infant death (PMID: 25904541, 19716085, 26746457, 28412158, 30086531, 29773157, 31737537); In vitro studies in cultured cells suggest that p.(E48K) functions similar to wild-type channels (PMID: 25904541); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28150151, 26746457, 29773157, 28412158, 30086531, 36693943, 19716085, 25904541, 31737537) -

Cardiac arrhythmia

Uncertain:2

Dec 02, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glutamic acid with lysine at codon 48 of the SCN5A protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant is found within a highly conserved N-terminus domain (a.a. 1-131). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals suspected of being affected with Brugada syndrome (PMID: 31737537) and in an individual affected with sudden infant death (PMID: 30086531). This variant has been identified in 17/278150 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. -

May 09, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Uncertain:1

Jun 04, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Glu48Lys vari ant in SCN5A has been reported in one individual with LQTS (Kapplinger 2009) and in 16/274964 of total chromosomes by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org; dbSNP rs199473048). Computational prediction to ols and conservation analysis do not provide strong support for or against an im pact to the protein; however, gorillas carry a lysine (Lys) at this position, ra ising the possibility that this change may be tolerated. In addition, in vitro s tudies suggest that this variant does not impact Nav1.5 channel function; howeve r, these types of assays may not accurately represent biological function (Kappl inger 2015; Anderson 2017). In summary, while the clinical significance of the p.Glu48Lys variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP criteria applied: BS1_supporting. -

Brugada syndrome 1

Uncertain:1

May 11, 2018

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Sep 07, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Primary dilated cardiomyopathy

Uncertain:1

Genetics and Genomics Program, Sidra Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Cardiovascular phenotype

Uncertain:1

Feb 26, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.142G>A (p.E48K) 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 142, causing the glutamic acid (E) at amino acid position 48 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital long QT syndrome

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 Long QT syndrome in the following publications (PMID:19716085). 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

0.067

CardioboostArm

Benign

0.0000078

CardioboostCm

Benign

0.0060

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

.;.;.;.;.;D;.;.;.;T;T

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.48

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

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.84

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

MetaSVM

Uncertain

0.046

MutationAssessor

Benign

1.9

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

PhyloP100

1.7

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.9

N;N;N;N;N;N;N;N;N;.;D

REVEL

Pathogenic

0.72

Sift

Benign

0.25

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

Sift4G

Benign

0.12

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

Polyphen

0.0020

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

Vest4

0.36

MutPred

0.74

Gain of ubiquitination at E48 (P = 0.0048);Gain of ubiquitination at E48 (P = 0.0048);Gain of ubiquitination at E48 (P = 0.0048);Gain of ubiquitination at E48 (P = 0.0048);Gain of ubiquitination at E48 (P = 0.0048);Gain of ubiquitination at E48 (P = 0.0048);Gain of ubiquitination at E48 (P = 0.0048);Gain of ubiquitination at E48 (P = 0.0048);Gain of ubiquitination at E48 (P = 0.0048);Gain of ubiquitination at E48 (P = 0.0048);Gain of ubiquitination at E48 (P = 0.0048);

MVP

0.77

MPC

0.56

ClinPred

0.050

GERP RS

2.7

PromoterAI

0.0052

Neutral

(source)

Varity_R

0.061

gMVP

0.64

Mutation Taster

=0/100

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over