rs727505158

chr3-38599004-TG-T

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.1936del(p.Gln646ArgfsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000223 in 1,612,010 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: SCN5A NM_001099404.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 4.83

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 3-38599004-TG-T is Pathogenic according to our data. Variant chr3-38599004-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 179829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38599004-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.1936del	p.Gln646ArgfsTer5	frameshift_variant	13/28	ENST00000413689.6
SCN5A	NM_000335.5	c.1936del	p.Gln646ArgfsTer5	frameshift_variant	13/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.1936del	p.Gln646ArgfsTer5	frameshift_variant	13/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.1936del	p.Gln646ArgfsTer5	frameshift_variant	13/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1459856 Hom.: 0 Cov.: 31 AF XY: 0.0000207 AC XY: 15 AN XY: 725802

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: 0.0000288

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

Gnomad4 AFR AF: 0.0000241

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	This sequence change creates a premature translational stop signal (p.Gln646Argfs*5) in the SCN5A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). This variant is present in population databases (rs727505158, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Brugada syndrome (PMID: 20129283, 22090166, 22370247). ClinVar contains an entry for this variant (Variation ID: 179829). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 17, 2019	PP1_strong, PM2_supporting, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2022	Previously reported in multiple unrelated individuals with Brugada syndrome (Kapplinger et al., 2010; Kanter et al., 2012; Park et al., 2012; Chatterjee et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22995932, 31447099, 34649698, 28008009, 21980601, 29652902, 27153395, 22090166, 33087929, 33164571, 32533187, 34135346, 20129283, 22370247) -

Brugada syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 26, 2014	The p.Gln646ArgfsX5 variant in SCN5A has been reported in 5 individuals with Bru gada syndrome (Kapplinger 2010, Kante 2012, Park 2012) and segregated with disea se in 21 affected relatives (clinical manifestations included arrhythmia, syncop e, cardiac arrest, or sudden death) from one family (Park 2012). This variant h as also been reported by other clinical laboratories in ClinVar (Variation ID:17 9829) and has been identified in 1/15412 European chromosomes in gnomAD (https:/ /gnomad.broadinstitute.org/). This variant is predicted to cause a frameshift, w hich alters the protein?s amino acid sequence beginning at position 646 and lead s to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function varian ts in SCN5A are most commonly associated with Brugada syndrome although overlap presentations including other SCN5A-related phenotypes (Long QT syndrome) have b een described (Remme 2013). In summary, the p.Gln646ArgfsX5 variant meets our cr iteria to be classified as pathogenic for autosomal dominant Brugada syndrome ba sed upon the predicted impact to the protein, segregation with disease and very low frequency in the general population. ACMG/AMP Criteria applied: PVS1; PS4_Su pporting; PP1_Strong; PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 23, 2023	This variant deletes 1 nucleotide in exon 13 of the SCN5A gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Brugada syndrome (PMID: 20129283, 22370247, 32268277, 32533187, 33164571), early repolarization disorder (PMID: 34649698), and ventricular fibrillation (PMID: 22090166). This variant has been identified in 1/31374 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Jan 17, 2019	- -

Brugada syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Mar 27, 2019

This variant causes a frameshift at codon 646 which subsequently introduces a premature stop codon at position 5 and is therefore predicted to result in loss of normal protein function. Loss of function is a known mechanism of disease in the SCN5A gene. This variant has been previously reported as a heterozygous change in patients with Brugada Syndrome (PMID: 20129283, 22090166, 22370247). This variant was found to segregate with disease in a large affected family: 21/35 family members tested were found to harbor the p.Gln646ArgfsTer5 variant, all carriers had an abnormal ECG while other clinical manifestations ranged in severity but included arrhythmia, syncope, cardiac arrest, or sudden death (PMID: 22370247). This variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (1/30926) and thus is presumed to be rare. Based on the available evidence, the c.1936del; p.Gln646ArgfsTer5 variant is classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 19, 2023

The c.1936delC pathogenic mutation, located in coding exon 12 of the SCN5A gene, results from a deletion of one nucleotide at nucleotide position 1936, causing a translational frameshift with a predicted alternate stop codon (p.Q646Rfs*5). This variant has been reported in association with Brugada syndrome, sudden cardiac arrest/death, ventricular arrhythmias, and early repolarization (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Kanter RJ et al. Circulation, 2012 Jan;125:14-22; Chatterjee D et al. Eur Heart J, 2020 Aug;41:2878-2890; Campuzano O et al. EBioMedicine, 2020 Apr;54:102732; Wijeyeratne YD et al. Circ Genom Precis Med, 2020 Dec;13:e002911; Zhang ZH et al. J Am Coll Cardiol, 2021 Oct;78:1603-1617). In one family, all twenty-one individuals with this variant had abnormal ECGs and manifested varying severities of dysrhythmia phenotypes (Park JK et al. Heart Rhythm, 2012 Jul;9:1090-6). In addition to the clinical data presented in the literature, 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. -

Sinoatrial node disorder;C1142166:Brugada syndrome;C1720824:Sudden cardiac arrest Pathogenic:1

Pathogenic, no assertion criteria provided

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Sep 18, 2019

This variant has been identified in 3 probands as part of our research program. The first proband had a diagnosis of Brugada Syndrome, the second proband survived a cardiac arrest but no diagnosis could be made and the third proband of European descent presented with sinus node disease. For further information please feel free to contact us. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs727505158; hg19: chr3-38640495;