ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620248 SCV000737757 likely pathogenic Cardiovascular phenotype 2017-12-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
CSER_CC_NCGL; University of Washington Medical Center RCV000148865 SCV000190609 uncertain significance Cardiac conduction defect, nonspecific 2014-06-01 no assertion criteria provided research
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.
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
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.
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.
Invitae RCV000469869 SCV000545046 pathogenic Brugada syndrome 2016-10-21 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). A different missense substitution at this codon (p.Arg225Pro) has been determined to be pathogenic (PMID: 24815523, 26022185). This suggests that the arginine residue is critical for SCN5A protein function and that other missense substitutions at this position may also be pathogenic. This variant identified in the SCN5A gene is located in the transmembrane DI-S4 region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. Experimental studies have suggested that this missense change leads to the creation of a gating pore current (PMID: 12574143, 25624448). For these reasons, this variant has been classified as Pathogenic.

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