rs199473284

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000335.5(SCN5A):c.4882C>T(p.Arg1628*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000496 in 1,613,956 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 3.94

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 70 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-38551487-G-A is Pathogenic according to our data. Variant chr3-38551487-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 264276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38551487-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.4885C>T	p.Arg1629*	stop_gained	Exon 28 of 28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.4882C>T	p.Arg1628*	stop_gained	Exon 28 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.4885C>T	p.Arg1629*	stop_gained	Exon 28 of 28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.4882C>T	p.Arg1628*	stop_gained	Exon 28 of 28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152068

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251298

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135818

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Oct 28, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with known or suspected Brugada syndrome in the published literature (PMID: 30050137, 20129283); Identified in a patient with possible long QT syndrome in the published literature (PMID: 27871843); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as the sodium current is abolished (PMID: 30050137, 25829473); Nonsense variant predicted to result in protein truncation, as the last 388 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 30050137, 30662450, 30193851, 30203441, 34649698, 33131149, 20129283, 27871843, 25829473) -

Oct 27, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Strong, PM1, PS3_Supporting -

Jul 04, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg1629*) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 388 amino acid(s) of the SCN5A protein. This variant is present in population databases (rs199473284, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Brugada syndrome (PMID: 20129283, 25829473). ClinVar contains an entry for this variant (Variation ID: 264276). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects SCN5A function (PMID: 25829473). This variant disrupts a region of the SCN5A protein in which other variant(s) (p.Glu1823Hisfs*10) have been determined to be pathogenic (PMID: 17897635, 18361072). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Brugada syndrome 1

Pathogenic:1

Mar 11, 2023

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brugada syndrome

Pathogenic:1

Mar 24, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 28 of the SCN5A gene, creating a premature translation stop signal in the last exon. This variant alters the sequence of transmembrane domain DIV (a.a. 1524-1772) and C-terminal region (a.a. 1773-2016) and is expected to disrupt SCN5A protein function. This variant has been reported in two individuals affected with Brugada syndrome (PMID: 20129283, 25829473). This variant has been identified in 2/251298 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SCN5A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Aug 31, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1629* pathogenic mutation (also known as c.4885C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 4885. This changes the amino acid from an arginine to a stop codon within coding exon 27. In a study of Brugada syndrome clinical genetic testing, this alteration was reported in one patient (Kapplinger JD et al. Heart Rhythm. 2010;7(1):33-46). In addition, a young adult with Brugada syndrome was described to be compound heterozygous for this mutation in conjunction with another SCN5A alteration on the opposite chromosome, and induced pluripotent stem cell-derived cardiomyocytes generated from this patient exhibited significantly reduced sodium current. The p.R1629* mutation co-segregated with disease from parent to child, and in vitro functional analyses indicated p.R1629* sodium channels have virtually no activity (Tan BY et al. Europace. 2015:1-8.doi:10.1093/europace/euv058; Ma D et al. Sci Rep. 2018;8:11246).Based on the available evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.93

Vest4

0.95

GERP RS

3.6

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