chr3-38603999-G-A

Position:

• chr3-38603999-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The NM_001099404.2(SCN5A):​c.1603C>T​(p.Arg535Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SCN5A NM_001099404.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 3.26

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 19 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 3-38603999-G-A is Pathogenic according to our data. Variant chr3-38603999-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 517279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603999-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.1603C>T	p.Arg535Ter	stop_gained	12/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.1603C>T	p.Arg535Ter	stop_gained	12/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.1603C>T	p.Arg535Ter	stop_gained	12/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.1603C>T	p.Arg535Ter	stop_gained	12/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 247858 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134558

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461302 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726900

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	May 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change creates a premature translational stop signal (p.Arg535*) 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 (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with SCN5A-related arrhythmia (PMID: 12106943, 20129283, 23631430). ClinVar contains an entry for this variant (Variation ID: 517279). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 07, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2021	Nonsense 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; Published functional studies demonstrate a damaging effect on channel function (Keller et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 517279; ClinVar); This variant is associated with the following publications: (PMID: 19606473, 23631430, 25525159, 19251209, 20129283, 28482396, 31043699, 30193851, 31447099, 33131149, 20031634, 15890323, 30662450, 34135346, 33087929, 12106943) -

SCN5A-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 20, 2023

The SCN5A c.1603C>T (p.Arg535Ter) nonsense variant results in the substitution of arginine at amino acid position 535 with a stop codon. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. Across a selection of the available literature, this variant has been identified in at least ten unrelated individuals - seven with Brugada syndrome, and one each with long QT syndrome, sudden infant death syndrome, and sudden adult cardiac death (PMID: 12106943; PMID: 15890323; PMID: 20031634; PMID: 20129283; PMID: 23631430; PMID: 25757662; PMID: 34076677). Segregation of the variant with the disorder was noted in at least one family (PMID: 20031634). This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000056 in the East Asian population (version 2.1.1). Based on the available evidence, the c.1603C>T (p.Arg535Ter) variant is classified as pathogenic for SCN5A-related disorders. -

Primary familial dilated cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

-

- -

Brugada syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 28, 2020

The p.Arg535X variant in SCN5A has been reported in at least 9 individuals (8 with Brugada syndrome and 1 referred for Long QT syndrome testing), and segregated with disease in 4 affected relatives from 1 family (Smits 2002, Keller 2005, Probst 2009, Meregalli 2009, Kapplinger 2010, Lieve 2013). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 517279) and has been identified in 0.006% (1/17212) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org/). This nonsense variant leads to a premature termination codon at position 535, which leads to a truncated protein that impacts protein function as shown by in vitro studies (Keller 2005). Heterozygous loss of function variants in the SCN5A gene have been reported in individuals with Brugada syndrome (Kapplinger 2010), DCM (Olson 2005), ventricular fibrillation (Chen 1998), as well as AV block and cardiac conduction defects (Baruteau 2012). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Brugada syndrome. ACMG/AMP criteria applied: PVS1, PM2, PS4_Moderate, PP1. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 16, 2023

The p.R535* pathogenic mutation (also known as c.1603C>T), located in coding exon 11 of the SCN5A gene, results from a C to T substitution at nucleotide position 1603. This changes the amino acid from an arginine to a stop codon within coding exon 11. This alteration has been reported in several Brugada syndrome (BrS) cohorts and has been shown to segregate with disease in one family (Probst V et al. Circ Cardiovasc Genet. 2009;2:552-7; Kapplinger JD et al. Heart Rhythm. 2010;7:33-46). It has also been detected in long QT syndrome (LQTS) and sudden infant death syndrome (SIDS) cohorts (Lieve KV et al. Genet Test Mol Biomarkers. 2013;17:553-61; Winkel BG et al. Heart Rhythm. 2015;12:1241-9). 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

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 03, 2023

This variant changes 1 nucleotide in exon 12 of the SCN5A gene, creating a premature translation stop signal. A functional study has shown that this variant results in a truncated protein and leads to a complete loss of sodium current (PMID: 15890323). This variant has been reported in over ten individuals affected with Brugada syndrome (PMID: 12106943, 15890323, 16643399, 19251209, 20031634, 32893267, 35331424) or suspected of having Brugada syndrome (PMID: 20129283, 35352813), and in an individual affected with sudden infant death syndrome (PMID: 25757662). This variant has been identified in 1/247858 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	49
DANN	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
Vest4		0.92
GERP RS		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.73		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1417036453; hg19: chr3-38645490; COSMIC: COSV61114969;