rs727505158

Variant names:

• chr3-38599004-TG-T
• rs727505158
• NM_001099404.2:c.1936delC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001099404.2(SCN5A):​c.1936delC​(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 (★★). Synonymous variant affecting the same amino acid position (i.e. Q646Q) has been classified as Likely benign. 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:12
• Conservation: PhyloP100: 4.83
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• Brugada syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Brugada syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1E

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• sick sinus syndrome 1

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial heart block, type 1A

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• atrial standstill

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sick sinus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal familial ventricular fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 3-38599004-TG-T is Pathogenic according to our data. Variant chr3-38599004-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 179829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099404.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	NM_001099404.2	MANE Plus Clinical	c.1936delC	p.Gln646ArgfsTer5	frameshift	Exon 13 of 28	NP_001092874.1
	SCN5A	NM_000335.5	MANE Select	c.1936delC	p.Gln646ArgfsTer5	frameshift	Exon 13 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.1936delC	p.Gln646ArgfsTer5	frameshift	Exon 13 of 28	NP_932173.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	ENST00000413689.6	TSL:5 MANE Plus Clinical	c.1936delC	p.Gln646ArgfsTer5	frameshift	Exon 13 of 28	ENSP00000410257.1
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.1936delC	p.Gln646ArgfsTer5	frameshift	Exon 13 of 28	ENSP00000398266.2
	SCN5A	ENST00000333535.9	TSL:1	c.1936delC	p.Gln646ArgfsTer5	frameshift	Exon 13 of 28	ENSP00000328968.4

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

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1110370

Other (OTH) AF: 0.0000332 AC: 2 AN: 60248

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

May 24, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Previously reported in multiple unrelated individuals with Brugada syndrome (PMID: 20129283, 22090166, 22370247, 32533187); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22995932, 31447099, 34649698, 28008009, 21980601, 29652902, 27153395, 22090166, 36007526, 33087929, 33164571, 32533187, 34135346, 34495297, 36136372, 36578016, 22370247, 20129283)

Dec 17, 2024

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.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.

Mar 17, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PM2_supporting, PVS1

Oct 16, 2020

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Brugada syndrome Pathogenic:3

Aug 23, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jan 17, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 26, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Brugada syndrome 1 Pathogenic:2

Jan 14, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction); Variant is present in gnomAD <0.001 for a dominant condition (v4: 36 heterozygote(s), 0 homozygote(s)) ; This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been previously reported in multiple patients with Brugada Syndrome (ClinVar, PMID: 20129283, 22090166) and in a family with variable arrhythmia phenotypes (PMID: 22370247); This variant has strong evidence for segregation with disease. It has been reported to segregate with variable arrhythmia phenotypes in a large family (PMID: 22370247); Many other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). Additional information: This variant is heterozygous; This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited; however, SSS is caused by biallelic variants (OMIM); Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome 1 (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome 3 (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss of function or gain of function mechanism (PMID: 29798782); Inheritance information for this variant is not currently available in this individual.

Mar 27, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Cardiac arrest;C0428908:Sinoatrial node disorder;C1142166:Brugada syndrome Pathogenic:1

Sep 18, 2019

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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.

Cardiovascular phenotype Pathogenic:1

May 19, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Cardiac arrhythmia Pathogenic:1

Aug 14, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.8
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs727505158; hg19: chr3-38640495;