ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.673C>T (p.Arg225Trp) (rs199473072)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182942 SCV000235338 pathogenic not provided 2018-07-23 criteria provided, single submitter clinical testing The R225W pathogenic variant in the SCN5A gene has been reported in association with Long QT syndrome, Brugada syndrome, sudden arrhythmia death syndrome (SADS), and other conduction disorders (Bezzina et al., 2003; Kapplinger et al., 2009; Meregalli et al., 2009; Probst et al., 2009; Kapplinger et al., 2010; Lahrouchi et al., 2017). Bezzina et al., (2003) initially described R225W in two infant siblings with severe conduction disease and wide QRS-complexes. A second SCN5A variant (W156X) was found in trans with R225W in both siblings; the parents, who had essentially normal cardiac studies, each harbored one of these two SCN5A variants (Bezzina et al., 2003). The R225W variant was subsequently reported to segregate with disease in several affected relatives from unrelated families with a history of Brugada syndrome and/or progressive cardiac conduction defects (PCCD) (Meregalli et al., 2009; Probst et al., 2009). This variant has also been identified in other unrelated individuals referred for arrhythmia genetic testing at GeneDx. Moreover, R225W is not observed at a significant frequency in large population cohorts (Lek et al., 2016).The R225W variant results in a non-conservative amino acid substitution within the in the S4 transmembrane voltage sensor helix. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, functional studies have demonstrated that R225W results in a significant reduction in sodium current amplitude as well as an alteration in gating pore current that is thought to lead to a gain of function (Bezzina et al., 2003; Moreau et al., 2015), although it is not clear how accurately these studies reflect in vivo conditions. Lastly, other pathogenic missense variants affecting the same residue (R225Q, R225P) have been published in association with cardiomyopathy, arrhythmia, and/or sudden death, and have also been shown to alter sodium channel function (Millat et al., 2006; Beckermann et al., 2014; Wang et al., 2014; Shen et al., 2017), further supporting the functional importance of this residue.In summary, R225W in the SCN5A gene is interpreted as a pathogenic variant.
Invitae RCV000469869 SCV000545046 pathogenic Brugada syndrome 2020-09-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 225 of the SCN5A protein (p.Arg225Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs199473072, ExAC 0.003%). This variant has been reported in an individual affected with cardiac conduction disease who was compound heterozygous for SCN5A p.Trp156Ter (PMID: 12574143). It was shown in individuals with Brugada syndrome (PMID: 19606473, 20031634), and was also seen in other individuals with SCN5A-related diseases (PMID: 19251209, 22885917). It was also observed in individuals referred for Brugada syndrome testing (PMID: 20129283) and long QT syndrome testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 68032). This variant disrupts the p.Arg225 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24815523, 26022185). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect SCN5A protein function (PMID: 12574143, 25624448). For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000521042 SCV000616615 pathogenic Long QT syndrome 3 2017-05-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620248 SCV000737757 pathogenic Cardiovascular phenotype 2020-06-18 criteria provided, single submitter clinical testing The p.R225W pathogenic mutation (also known as c.673C>T), located in coding exon 5 of the SCN5A gene, results from a C to T substitution at nucleotide position 673. The arginine at codon 225 is replaced by tryptophan, an amino acid with dissimilar properties, and is located in the DI-S4 transmembrane region. This variant was previously described in conjunction with another SCN5A alteration in compound heterozygous siblings, both of whom were diagnosed with severe cardiac conduction disease after birth. One of these siblings also developed severe dilated cardiomyopathy (DCM) and died at 1 year of age (Bezzina CR et al. Circ Res. 2003;92:159-68). In another family, this variant was reported in multiple individuals with progressive cardiac conduction disease (PCCD) and/or Brugada syndrome (BrS), although a relative negative for this alteration also exhibited PCCD (Probst V et al. Circ Cardiovasc Genet. 2009;2:552-7). This alteration has also been reported in sudden cardiac death, BrS, and LQTS cohorts (Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303​; Kapplinger JD et al. Heart Rhythm. 2010;7:33-46; Lahrouchi N et al. J. Am. Coll. Cardiol. 2017 May;69(17):2134-2145). Multiple in vitro functional analyses indicate that this variant impacts protein function (Bezzina CR et al. Circ. Res. 2003;92:159-68; Moreau A et al. J Gen Physiol. 2015;145:93-106; Strege PR et al. Am. J. Physiol. Gastrointest. Liver Physiol. 2018;314:G494-G503). In addition, based on internal structural assessment, this alteration is predicted to disrupt the voltage sensing motif in voltage sensing domain 1 (Jiang D et al. Cell. 2020;01;180(1):122-134.e10). Other alterations affecting the same amino acid, p.R225Q (c.674G>A) and p.R225P (c.674G>C), have been reported in patients with complex arrhythmias and multifocal ventricular ectopy (Millat G et al. Clin Genet. 2006;70:214-27; Beckermann TM et al. Heart Rhythm. 2014;11:1446-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000521042 SCV000840064 pathogenic Long QT syndrome 3 2017-07-05 criteria provided, single submitter clinical testing This c.673C>T (p.Arg225Trp) variant has been reported in 7 patients with Brugada syndrome from 2 families [PMID 19251209]. This variant was also reported in two siblings with severe conduction disease compound heterozygous for this variant and p.Trp146* variant [PMID 12574143]. The mother however, who was a carrier for this variant, was clinically asymptomatic with normal ECG. Functional assay showed that this variant affects the sodium channel voltage gating. Variants affecting the same amino acid (p.Arg225Gln and p.Arg225Pro) have been reported in additional patients with arrythmias indicating the functional importance of this amino acid and its position [PMID 16922724, 26733869]. This variant was reported in one heterozygous individuals from Europe (http://exac.broadinstitute.org/variant/3-38655264-G-A). This variant is highly conserved in mammals. While not validated for clinical use, computer-based algorithms predict this p.Arg225Trp change to be deleterious. It is thus classified as a pathogenic variant.
Color Health, Inc RCV001190163 SCV001357589 likely pathogenic Arrhythmia 2020-05-24 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 225 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental studies have shown that this variant causes a significant reduction in sodium current (PMID: 12574143, 19251209). This variant has been reported in two siblings affected with severe, early-onset conduction disease, who were compound heterozygous for this variant and p.Trp156* in the same gene (PMID: 12574143). In this study, this variant was inherited from the siblings' mother, who had valve abnormality but otherwise asymptomatic. This variant has been reported in over ten individuals affected with Brugada syndrome from three families (PMID: 19251209, 20031634) and was also observed in two children affected with cardiac conduction disease (PMID: 22885917). This variant has also been observed in three individuals referred for Brugada syndrome testing (PMID: 20129283) and four individuals referred for long QT syndrome testing (PMID: 19716085). This variant has been identified in 6/273472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058835 SCV000090355 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington RCV000148865 SCV000190609 uncertain significance Cardiac conduction defect, nonspecific 2014-06-01 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.