rs1553695282

Positions:

• chr3-38560245-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000423572.7(SCN5A):​c.4144C>T​(p.Gln1382Ter) variant causes a stop gained change involving the alteration of a non-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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN5A ENST00000423572.7 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.78

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-38560245-G-A is Pathogenic according to our data. Variant chr3-38560245-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38560245-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.4147C>T	p.Gln1383Ter	stop_gained	23/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.4144C>T	p.Gln1382Ter	stop_gained	23/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.4147C>T	p.Gln1383Ter	stop_gained	23/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.4144C>T	p.Gln1382Ter	stop_gained	23/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2016	The Q1383X variant in the SCN5A gene has been reported in a man diagnosed at age 40 with Brugada syndrome who also harbored a L619F variant in the SCN5A gene that was reported to be pathogenic (Kapplinger et al., 2010). Although it was not reported if these variants were in cis or trans, Kapplinger et al. (2010) found that both the Q1383X and L619F variants were absent in >2600 control alleles. Moreover, the Q1383X likely pathogenic variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the SCN5A gene have been reported in HGMD in association with Brugada syndrome (Stenson et al., 2014). Furthermore, the Q1383X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2018	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). This variant has been reported in an individual referred for testing for Brugada syndrome (PMID: 20129283). ClinVar contains an entry for this variant (Variation ID: 431948). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln1383*) in the SCN5A gene. It is expected to result in an absent or disrupted protein product. -

Brugada syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jul 29, 2024

This variant changes 1 nucleotide in exon 23 of the SCN5A gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has been reported in individual(s) affected with Brugada syndrome (PMID: 20129283, 32893267). This variant has not been identified 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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2024

The p.Q1383* pathogenic mutation (also known as c.4147C>T), located in coding exon 22 of the SCN5A gene, results from a C to T substitution at nucleotide position 4147. This changes the amino acid from a glutamine to a stop codon within coding exon 22. This alteration was detected in an individual with Brugada syndrome who also harbored an additional SCN5A alteration (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, 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	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Benign	0.67	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
Vest4		0.96
GERP RS		3.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1553695282; hg19: chr3-38601736;