ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.4978G>A (p.Gly1660Arg) (rs199473292)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000183094 SCV000927750 uncertain significance not provided 2018-06-15 criteria provided, single submitter clinical testing
GeneDx RCV000183094 SCV000235504 uncertain significance not provided 2017-02-10 criteria provided, single submitter clinical testing The G1661R variant resulting from one of two different nucleotide substitutions (c.4981 G>A, c.4981 G>C) has been reported in three individuals with clinically suspected Brugada syndrome and was absent in greater than 2,600 reference alleles (Kapplinger et al., 2010). However, specific clinical, family history and segregation data was not provided. Additionally, while this variant has been reported in multiple individuals who had DNA-based testing for arrhythmia at GeneDx, co-segregation with arrhythmia has not been confirmed amongst related individuals and many referrals lacked informative clinical information. Therefore, the information obtained from these individuals is not sufficient and additional family studies are essential for full interpretation. Nonetheless, the G1661R 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. The G1661R 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, located in the S5 transmembrane helix of repeat IV, occurs at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, additional evidence is needed to determine whether this variant is pathogenic or benign.
Invitae RCV000554082 SCV000637168 uncertain significance Brugada syndrome 2017-03-06 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1661 of the SCN5A protein (p.Gly1661Arg). 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 (rs199473292, ExAC no frequency). This variant has been reported in individuals affected with Brugada syndrome (PMID: 20129283). ClinVar contains an entry for this variant (Variation ID: 201523). 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. This variant identified in the SCN5A gene is located in the transmembrane DIV-S5 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. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000554082 SCV000748006 likely pathogenic Brugada syndrome 2016-12-22 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000183094 SCV000924946 uncertain significance not provided 2017-03-29 no assertion criteria provided provider interpretation

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.