rs886037903

chr3-38551014-CAG-C

Variant summary

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

The NM_001099404.2(SCN5A):c.5356_5357del(p.Leu1786GlufsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCN5A NM_001099404.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.31

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 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 50 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-38551014-CAG-C is Pathogenic according to our data. Variant chr3-38551014-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 254156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38551014-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_000335.5	c.5353_5354del	p.Leu1785GlufsTer2	frameshift_variant	28/28	ENST00000423572.7
SCN5A	NM_001099404.2	c.5356_5357del	p.Leu1786GlufsTer2	frameshift_variant	28/28	ENST00000413689.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.5356_5357del	p.Leu1786GlufsTer2	frameshift_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.5353_5354del	p.Leu1785GlufsTer2	frameshift_variant	28/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461894 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2022	Reported as a maternally-inherited variant in a child who presented with atrial flutter and ventricular tachycardia without structural heart disease; the mother also demonstrated atrial flutter and sick sinus syndrome (Abe et al., 2014); Frameshift variant predicted to result in protein truncation, as the last 231 amino acids are replaced with 1 different amino acid, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24762805, 33131149, 29728395, 16643399, 33164571, 20129283, 30662450, 28781330, 30193851) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 06, 2023	This sequence change creates a premature translational stop signal (p.Leu1786Glufs*2) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 231 amino acid(s) of the SCN5A protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of Brugada syndrome (PMID: 20129283, 24762805, 30193851). ClinVar contains an entry for this variant (Variation ID: 254156). This variant disrupts a region of the SCN5A protein in which other variant(s) (p.Glu1867*) have been determined to be pathogenic (PMID: 16267250, 19406494, 24895455; Invitae). 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Medical Genetics Ghent, University of Ghent

Jan 01, 2016

This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server) and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. -

Brugada syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 15, 2023

This variant deletes 2 nucleotides in exon 28 of the SCN5A gene, creating a frameshift and premature translation stop signal in the last exon. This variant is expected to result in a truncated protein product. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncation variants occurring C-terminal to this variant have been reported in individuals affected with long QT syndrome (Clinvar). Loss of SCN5A function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiac arrhythmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 02, 2019

This variant deletes 2 nucleotides in exon 28 of the SCN5A gene, creating a frameshift and premature translation stop signal in the last exon. This variant is expected to result in a truncated protein product. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncation variants occurring C-terminal to this variant have been reported in individuals affected with long QT syndrome (Clinvar). Loss of SCN5A function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs886037903; hg19: chr3-38592505;