3-38613782-G-A

Position:

• chr3-38613782-G-A

Variant summary

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

The NM_000335.5(SCN5A):​c.664C>T​(p.Arg222Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000206 in 1,458,286 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SCN5A NM_000335.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 3.94

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 3-38613782-G-A is Pathogenic according to our data. Variant chr3-38613782-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 201438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38613782-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_000335.5	c.664C>T	p.Arg222Ter	stop_gained	6/28	ENST00000423572.7
SCN5A	NM_001099404.2	c.703+193C>T		intron_variant		ENST00000413689.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000423572.7	c.664C>T	p.Arg222Ter	stop_gained	6/28	1	NM_000335.5	A1
SCN5A	ENST00000413689.6	c.703+193C>T		intron_variant		5	NM_001099404.2	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458286 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725044

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2022	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 in Xenopus oocytes demonstrate a loss-of-function effect (Ortiz-Bonnin et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 32048431, 34461752, 26467377, 19716085, 26173111, 27232914, 20129283, 27287068, 22277643, 29728395, 30193851, 31447099, 34446689, 35492839, 33131149) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 23, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 201438). This premature translational stop signal has been observed in individual(s) with Brugada syndrome (PMID: 19716085, 26173111, 26467377, 27287068). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg222*) 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). -

Brugada syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 18, 2023	This variant changes 1 nucleotide in exon 6 of the SCN5A gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has shown that this variant causes a large reduction of sodium current amplitudes when expressed in Xenopus oocytes (PMID 27287068). This variant has been reported in at least five families affected with Brugada syndrome (PMID: 22277643, 26173111, 26467377, 27232914, 27287068, 32893267, 34546463). Asymptomatic carriers were also reported in a few families (PMID: 22277643, 26467377). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Dec 17, 2019	This c.664C>T (p.Arg222*) variant in the SCN5A gene introduces a premature translation termination codon. This variant has been observed in multiple individuals with Brugada syndrome as well as one individual tested for Long QT syndrome (PMID 26173111, 20129283, 27287068, 27232914, and 26467377). Based on the current evidence, this variant in the SCN5A gene is classified as pathogenic. -

SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 17, 2021

- -

Long QT syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Apr 27, 2018

This c.664C>T (p.Arg222*) variant in the SCN5A gene introduces a premature translation termination codon. This variant has been observed in multiple individuals with Brugada syndrome as well as one individual tested for Long QT syndrome (PMID 26173111, 20129283, 27287068, 27232914, and 26467377). Based on the current evidence, this variant in the SCN5A gene is classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2021

The p.R222* pathogenic mutation (also known as c.664C>T), located in coding exon 5 of the SCN5A gene, results from a C to T substitution at nucleotide position 664. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has been detected in several unrelated individuals with diagnosed or suspected Brugada syndrome and has shown some segregation with disease features in families (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Santos LF et al. Europace, 2012 Jun;14:882-8; Ortiz-Bonnin B et al. Pflugers Arch, 2016 08;468:1375-87; Asadi M et al. Anatol J Cardiol, 2016 Mar;16:170-4; Berthome P et al. Heart Rhythm, 2019 02;16:260-267; Selga E et al. PLoS One, 2015 Jul;10:e0132888). This mutation has also been detected in a long QT syndrome genetic testing cohort and in cohorts not selected for the presence of arrhythmia; however, details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Zouk et al. Am J Hum Genet, 2019 09;105:588-605; Diebold I et al. Hum Mutat, 2020 05;41:1025-103). One in vitro functional study reported this variant to produce no detectable sodium current (Ortiz-Bonnin B et al. Pflugers Arch, 2016 08;468:1375-87). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jul 24, 2023

This variant changes 1 nucleotide in exon 6 of the SCN5A gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has shown that this variant causes a large reduction of sodium current amplitudes when expressed in Xenopus oocytes (PMID 27287068). This variant has been reported in at least five families affected with Brugada syndrome (PMID: 22277643, 26173111, 26467377, 27232914, 27287068, 32893267, 34546463). Asymptomatic carriers were also reported in a few families (PMID: 22277643, 26467377). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Benign	0.11
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	A;A;A;A;D;D;D;D;D;D
Vest4		0.89
GERP RS		4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.36		Position offset: -39

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

Publications

LitVar

Other links and lift over

dbSNP: rs794728849; hg19: chr3-38655273; COSMIC: COSV61140413; COSMIC: COSV61140413;