ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.664C>T (p.Arg222Ter) (rs794728849)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182937 SCV000235332 pathogenic not provided 2018-10-12 criteria provided, single submitter clinical testing The R222X pathogenic variant in the SCN5A gene has been published numerous times in association with Brugada syndrome (Kapplinger et al., 2010; Santos et al., 2012; Selga et al., 2015, Calvo et al., 2016, Ortiz-Bonnin et al., 2016) and has been found to segregate with disease though multiple generations of a large Portuguese family (Santos et al., 2012). In addition, R222X has been reported in an individual referred for LQTS genetic testing, although no clinical or segregation data was provided (Kapplinger et al., 2009). Furthermore, R222X is not observed in large population cohorts (Lek et al., 2016). The R222X variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Functional studies with Xenopus ooctyes demonstrated that R222X resulted in complete loss of function of the NaV1.5 channel, supporting that haploinsufficiency is the mechanism of disease (Ortiz-Bonnin et al., 2016). Moreover, many other nonsense variants in the SCN5A gene have been reported in association with Brugada syndrome in the Human Gene Mutation Database (Stenson et al., 2014). In summary, R222X in the SCN5A gene is interpreted as a pathogenic variant.
Gharavi Laboratory,Columbia University RCV000182937 SCV000809445 pathogenic not provided 2018-09-16 no assertion criteria provided research
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.
Invitae RCV000539108 SCV000637201 pathogenic Brugada syndrome 2017-08-18 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several families and individuals affected with Brugada syndrome (PMID: 26173111, 26467377, 27287068), and individuals referred for long QT testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 201438). Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). For these reasons, this variant has been classified as Pathogenic.

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