ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.4891C>T (p.Arg1631Cys) (rs878855292)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000431928 SCV000517352 pathogenic not provided 2017-08-23 criteria provided, single submitter clinical testing R1632C in the SCN5A gene has been reported in a 17-year-old male with a history of syncope afterexercise; presenting with atrial tachycardia, sinus node dysfunction and Brugada syndrome (Nakajima etal., 2015). R1632C was identified in the proband's mother who had a personal history of syncope andBrugada pattern on ECG after drug challenge. Additionally, R1632C was absent in 200 control alleles.R1632C is located in the DIV-S4 voltage sensor and in-vitro functional studies revealed R1632C results inenhanced fast-inactivated state stability due to delayed recovery from fast inactivation, resulting in loss ofsodium channel availability (Nakajima et la., 2015). The R1632C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, the R1632C 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. This substitution occurs at a position that is conserved across species and in silico analysispredicts this variant is probably damaging to the protein structure/function. Furthermore, several missensevariants in nearby residues (R1626P, R1626H, R1629G, R1629Q, G1631D) including one at the sameresidue (R1632H) have been reported in the Human Gene Mutation Database (HGMD) in association witharrhythmia (Stenson et al., 2014), supporting the functional importance of this region of the protein.In summary, R1632C in the SCN5A gene is interpreted as a pathogenic variant.
Invitae RCV000233617 SCV000291812 uncertain significance Brugada syndrome 2018-02-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1632 of the SCN5A protein (p.Arg1632Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a single family affected with Brugada syndrome (BrS) (PMID: 26031372). However, there are not enough affected individuals in this family to confirm segregation. Experimental studies have shown that this missense change enhances the fast-inactivated state stability of the sodium channel, but the clinical significance of this finding is uncertain (PMID: 26031372). In summary, this variant is absent from population databases, has been found previously in a patient with BrS and has been reported to have an effect on protein function. However, in the absence of conclusive segregation or functional studies, at this time this change has been classified as a Variant of Uncertain Significance.

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