rs775576991

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_001099404.2(SCN5A):c.1597C>T(p.Arg533Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,360 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R533H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 2.68

Publications

7 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, 0.877

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.1597C>T	p.Arg533Cys	missense_variant	Exon 12 of 28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.1597C>T	p.Arg533Cys	missense_variant	Exon 12 of 28	ENST00000423572.7	NP_000326.2	Q14524-2Q86V90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 link	c.1597C>T	p.Arg533Cys	missense_variant	Exon 12 of 28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.1597C>T	p.Arg533Cys	missense_variant	Exon 12 of 28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152180

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000808

AC:

AN:

247436

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000583

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000890

AC:

AN:

1461180

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726814

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.0000448

AC:

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000900

AC:

AN:

1111626

Other (OTH)

AF:

0.0000166

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.537

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000162

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

Jul 09, 2019

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with cysteine at codon 533 of the SCN5A protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/278818 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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

Aug 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Brugada syndrome

Uncertain:1

Aug 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 533 of the SCN5A protein (p.Arg533Cys). This variant is present in population databases (rs775576991, gnomAD 0.006%). This missense change has been observed in individual(s) with long QT syndrome as compound heterozygous with another variant in SCN5A and/or SCN5A-related conditions (PMID: 27485560, 30847666). ClinVar contains an entry for this variant (Variation ID: 575108). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -

not provided

Uncertain:1

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SCN5A: PM2 -

Cardiovascular phenotype

Uncertain:1

Dec 07, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R533C variant (also known as c.1597C>T), located in coding exon 11 of the SCN5A gene, results from a C to T substitution at nucleotide position 1597. The arginine at codon 533 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was detected in an arrhythmia genetic testing cohort; however, clinical details were limited (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is 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

0.13

CardioboostArm

Benign

0.012

CardioboostCm

Benign

0.063

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

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

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.88

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

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

PhyloP100

2.7

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-6.2

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

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.018

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

Polyphen

1.0

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

Vest4

0.64

MutPred

0.43

Loss of loop (P = 0.0022);Loss of loop (P = 0.0022);Loss of loop (P = 0.0022);Loss of loop (P = 0.0022);Loss of loop (P = 0.0022);Loss of loop (P = 0.0022);Loss of loop (P = 0.0022);Loss of loop (P = 0.0022);Loss of loop (P = 0.0022);

MVP

0.88

MPC

1.3

ClinPred

0.95

GERP RS

4.3

Varity_R

0.47

gMVP

0.69

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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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rs775576991

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over