ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.4912C>T (p.Arg1638Ter) (rs761505217)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000627225 SCV000748214 pathogenic not provided 2018-02-16 criteria provided, single submitter clinical testing The R1638X variant has been published in multiple individuals with SCN5A-related arrhythmias or referred for arrhythmia testing (Mergalli et al., 2006; Mergalli et al., 2009; Kapplinger et al., 2010; Amin et al., 2011; Nannenberg et al., 2012; Kosmidis et al.; 2016). The R1638X variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay, in a gene for which loss-of-function is a known mechanism of disease. Furthermore, functional analysis using human-induced pluripotent stem cell–derived cardiomyocytes showed, in the presence of R1638X, a reduction of current through the SCN5A-associated sodium channel in comparison to wild-type cells (Kosmidis et al.; 2016). Other downstream nonsense and frameshift variants in the SCN5A gene have been reported in Human Gene Mutation Database in association with hereditary arrhythmia (Stenson et al., 2014). Furthermore, the R1638X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).In summary, R1638X in the SCN5A gene is interpreted as a pathogenic variant.
Invitae RCV001066521 SCV001231534 pathogenic Brugada syndrome 2019-01-31 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SCN5A gene (p.Arg1638*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 379 amino acids of the SCN5A protein. This variant is present in population databases (rs761505217, ExAC 0.004%). This variant has been observed in several individuals with clinical features of Brugada syndrome (PMID: 16764707, 20129283). ClinVar contains an entry for this variant (Variation ID: 523778). This variant disrupts the C-terminus of the SCN5A protein. Other variant(s) that disrupt this region (p.Arg1944*, p.Arg1958*, p.Tyr1995*) have been determined to be pathogenic (PMID: 19862833, 23936059, 24388587, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001066521 SCV001365636 likely pathogenic Brugada syndrome 2019-03-26 criteria provided, single submitter clinical testing The p.Arg1638X variant in SCN5A has been reported in at least 5 heterozygous individuals with Brugada syndrome (Meregali 2006, Kapplinger 2010). This variant was also reported by other clinical laboratories in ClinVar (Variation ID 523778) and has been identified in 0.002% (2/113722) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 1638. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. While the effect on the protein is unknown, functional studies using patient cells provide some evidence that the p.Arg1623X variant causes a loss of function (Kosmidis 2016). Additionally, numerous nonsense and frameshift variants downstream of this variant have been reported in affected individuals. Heterozygous loss of function variants of the SCN5A gene have been previously reported for DCM (Olson 2005), Brugada syndrome (Kapplinger 2010), ventricular fibrillation (Chen 1998), and atrioventricular block and cardiac conduction defects (Baruteau 2012). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Brugada syndrome based upon low frequency in controls, presence in multiple affected individuals, functional evidence and predicted impact to the protein. ACMG/AMP Criteria applied: PVS1_Strong, PM2, PS4_Supporting.

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.