rs863225273

Positions:

• chr3-38554320-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000423572.7(SCN5A):​c.4769G>A​(p.Trp1590Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN5A ENST00000423572.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.86

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 157 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-38554320-C-T is Pathogenic according to our data. Variant chr3-38554320-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 217838.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.4772G>A	p.Trp1591Ter	stop_gained	27/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.4769G>A	p.Trp1590Ter	stop_gained	27/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.4772G>A	p.Trp1591Ter	stop_gained	27/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.4769G>A	p.Trp1590Ter	stop_gained	27/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 13, 2024	This variant changes 1 nucleotide in exon 27 of the SCN5A gene, creating a premature translation stop signal. 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 or suspected of having Brugada syndrome (PMID: 20129283, ClinVar SCV000256663.2). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Multiple truncation variants occurring downstream of this variant are known to be disease-causing (ClinVar variation ID: 264276, 9374), suggesting that the impacted region is critical for SCN5A protein function. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Jul 01, 2015	The SCN5A Trp1591* variant was identified in our proband (an Asian male with Brugada syndrome). The proband presented with multiple syncopal episodes and was found to have spontaneous type 1 Brugada pattern. The SCN5A Trp1591* variant is absent from both the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). The variant was identified in 1 unrelated individual with Brugada syndrome in an international consortium of SCN5A mutations (Kapplinger J. et al., 2010). Loss-of-function in SCN5A is well established as a mechanism of disease in Brugada syndrome (Baroudi G. et al., 2004). Therefore, we have classified this variant as "pathogenic". -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	44
DANN	Uncertain	0.99
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
Vest4		0.93
GERP RS		3.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs863225273; hg19: chr3-38595811; COSMIC: COSV61140869;