ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.5227G>A (p.Gly1743Arg) (rs199473305)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183109 SCV000235519 pathogenic not provided 2018-12-10 criteria provided, single submitter clinical testing The G1743R pathogenic variant in the SCN5A gene has been reported previously multiple times in association with Brugada syndrome (Takahata et al., 2003; Valdivia et al., 2004; Hermida et al., 2010; Kapplinger et al., 2010; Crotti et al., 2012; Garcia-Molina et al., 2013; Chiang et al., 2015). The G1743R variant is not observed in large population cohorts (Lek et al., 2016). The G1743R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies demonstrated that G1743R significantly reduced plasma membrane expression of the Nav1.5 sodium channel and reduced sodium current in vitro (Chakrabarti et al., 2013; Valdivia et al., 2004). Another missense variant at the same residue (G1743E) has been reported in association with Brugada syndrome (Smits et al., 2002; Kapplinger et al., 2010), supporting the functional importance of this region of the protein. We interpret G1743R as a pathogenic variant.
Invitae RCV000058753 SCV000637174 pathogenic Brugada syndrome 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1743 of the SCN5A protein (p.Gly1743Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Brugada syndrome and to segregate with this disease in a family (PMID: 12639704, 15023552, 22984773, 25904541). ClinVar contains an entry for this variant (Variation ID: 67967). Experimental studies have shown that this missense change significantly diminishes SCN5A protein trafficking to the cell membrane (PMID: 15023552, 23420830). For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058753 SCV000090273 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:12639704;PMID:15023552;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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