rs199473622

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_001099404.2(SCN5A):c.4826C>T(p.Ser1609Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000807 in 1,610,018 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S1609W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 9.99

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.4826C>T	p.Ser1609Leu	missense_variant	Exon 28 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 link	c.4823C>T	p.Ser1608Leu	missense_variant	Exon 28 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.4826C>T	p.Ser1609Leu	missense_variant	Exon 28 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7 link	c.4823C>T	p.Ser1608Leu	missense_variant	Exon 28 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes

AF:

0.00000665

AC:

AN:

150378

Hom.:

Cov.:

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250002

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1459640

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726112

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33160

American (AMR)

AF:

0.00

AC:

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26062

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39600

South Asian (SAS)

AF:

0.00

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53006

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000990

AC:

AN:

1110984

Other (OTH)

AF:

0.00

AC:

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.00000665

AC:

AN:

150378

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40746

American (AMR)

AF:

0.00

AC:

AN:

15096

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5030

South Asian (SAS)

AF:

0.00

AC:

AN:

4690

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10502

Middle Eastern (MID)

AF:

0.00

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67622

Other (OTH)

AF:

0.00

AC:

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1609 of the SCN5A protein (p.Ser1609Leu). This variant is present in population databases (rs199473622, gnomAD 0.003%). This missense change has been observed in individual(s) with sudden unexpected death in infancy (PMID: 25757662). ClinVar contains an entry for this variant (Variation ID: 919932). 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: 25757662). 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. -

Oct 21, 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 has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25757662, 31043699) -

Cardiac arrhythmia

Uncertain:2

Aug 09, 2021

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces serine with leucine at codon 1609 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an infant affected with sudden death (PMID: 25757662). This variant has been identified in 3/250002 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. -

Nov 30, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Jul 30, 2020

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S1609L variant (also known as c.4826C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 4826. The serine at codon 1609 is replaced by leucine, an amino acid with dissimilar properties, and is located in the transmembrane DIV-S3 domain. This variant was reported in a sudden infant death cohort, but clinical details were not provided; limited functional studies suggested possible electrophysiological effects but the clinical impact is uncertain (Winkel BG et al. Heart Rhythm, 2015 Jun;12:1241-9). 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

Pathogenic

0.74

CardioboostArm

Uncertain

0.33

CardioboostCm

Benign

0.011

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

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

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.89

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

M_CAP

Pathogenic

0.48

MetaRNN

Uncertain

0.74

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

MetaSVM

Pathogenic

1.2

MutationAssessor

Uncertain

2.8

.;.;.;.;.;M;.;.;.

PhyloP100

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.4

D;D;D;D;D;D;N;D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

D;D;D;D;D;D;T;D;D

Sift4G

Uncertain

0.012

D;D;D;D;D;D;T;D;D

Polyphen

0.37

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

Vest4

0.57

MutPred

0.59

.;.;Loss of methylation at K1614 (P = 0.0759);.;.;Loss of methylation at K1614 (P = 0.0759);.;.;.;

MVP

0.94

MPC

0.64

ClinPred

0.84

GERP RS

4.5

Varity_R

0.73

gMVP

0.98

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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