ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5536C>T (p.Arg1846Cys) (rs768246863)

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 RCV000587038 SCV000571160 uncertain significance not provided 2017-03-07 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN5A gene. The R1847C variant has not beenpublished as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was notobserved in approximately 6,400 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. The R1847C variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differin polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across speciesand in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore,missense variants in nearby residues (H1849R, C1850S) and at the same residue (R1847H) have been reported in theHuman Gene Mutation Database in association with arrhythmia (Stenson et al., 2014). However, to our knowledgeno studies have been performed to determine the functional effect of the R1847C variant.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Integrated Genetics/Laboratory Corporation of America RCV000587038 SCV000700040 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing Variant summary: The c.5539C>T (p.Arg1847Cys) in SCN5A gene is a missense change that involves a conserved nucleotide. The variant is located within voltage-dependent L-type calcium channel, IQ-associated domain. 4/4 in silico tools predict benign outcome (SNPandGO not captured due to low reliability index), however no functional studies supporting these predictions were published at the time of evaluation. The variant is present in the large control population dataset of ExAC at a frequency of 0.00000828 (3/120772 chrs tested). This frequency does not exceed the maximal expected frequency of a pathogenic allele (0.00016) in this gene. The c.5539C>T has not, to our knowledge, been reported in affected individuals via published reports, but is cited as a VUS by a clinical laboratory. Taking all lines of evidence into consideration, the variant has been classified as a "Variant of Uncertain Significance (VUS)," until more information becomes available.
Invitae RCV000541591 SCV000637184 uncertain significance Brugada syndrome 2017-05-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1847 of the SCN5A protein (p.Arg1847Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs768246863, ExAC 0.009%) but has not been reported in the literature in individuals with a SCN5A-related disease. This variant identified in the SCN5A gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. It is unclear how this variant impacts the function of this protein. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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.