ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.4894C>T (p.Arg1632Cys) (rs878855292)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000233617 SCV000291812 pathogenic Brugada syndrome 2019-12-23 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 has been observed in individual(s) with Brugada syndrome (PMID: 26031372, 27082542, 31191357). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 242199). This variant has been reported to affect SCN5A protein function (PMID: 26031372). For these reasons, this variant has been classified as Pathogenic.
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.

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.