Submissions for variant NM_000335.5(SCN5A):c.664C>T (p.Arg222Ter)

dbSNP: rs794728849

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182937	SCV000235332	pathogenic	not provided	2022-11-20	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000182937	SCV000637201	pathogenic	not provided	2022-12-23	criteria provided, single submitter	clinical testing	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).
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000709764	SCV000840067	pathogenic	Long QT syndrome 3	2018-04-27	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002362939	SCV002662216	pathogenic	Cardiovascular phenotype	2021-10-11	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV002485217	SCV002788078	pathogenic	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2021-11-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003591705	SCV004362237	pathogenic	Cardiac arrhythmia	2023-07-24	criteria provided, single submitter	clinical testing	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.
All of Us Research Program, National Institutes of Health	RCV003996808	SCV004843403	pathogenic	Brugada syndrome	2023-09-18	criteria provided, single submitter	clinical testing	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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV003996808	SCV005045706	pathogenic	Brugada syndrome	2019-12-17	criteria provided, single submitter	clinical testing	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.
Gharavi Laboratory, Columbia University	RCV000182937	SCV000809445	pathogenic	not provided	2018-09-16	no assertion criteria provided	research