ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.1567C>T (p.Arg523Cys) (rs199473119)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000239767 SCV000235376 uncertain significance not provided 2016-03-28 criteria provided, single submitter clinical testing The R523C variant was identified in one Norwegian individual with a possible diagnosis of LQTS, however, specific medical history, family history and segregation data was not provided (Berge et al., 2008). In addition, Aurlien et al. (2009) reported R523C in a woman with idiopathic epilepsy who died of sudden unexpected death in epilepsy (SUDEP) at 25 years old. However, although authors speculate that this variant may have played a role in death by predisposition to both epilepsy and arrhythmia, this individual was never evaluated for cardiac involvement. In addition, the patient was treated with lamotrigine which may interfere with cardiac ion channels and potentially induce a terminal cardiac arrhythmia (Aurlien et al., 2009). The R523C variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Moreover, R523C 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. However, this substitution occurs at a position that is not conserved across species, and Cysteine is present in the Tenrec. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign
UCLA Clinical Genomics Center, UCLA RCV000196670 SCV000255459 likely pathogenic Brugada syndrome 1; Long QT syndrome 3; Progressive familial heart block, type 1A; Paroxysmal familial ventricular fibrillation 1; Dilated cardiomyopathy 1E; Atrial fibrillation, familial, 10 2012-12-04 criteria provided, single submitter clinical testing
Invitae RCV000464270 SCV000545031 uncertain significance Brugada syndrome 2018-05-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 523 of the SCN5A protein (p.Arg523Cys). 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 individual referred for long QT syndrome testing and another individual with epilepsy who died unexpectedly. Currently there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 18752142, 18752973). ClinVar contains an entry for this variant (Variation ID: 67667). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV001176300 SCV001340217 uncertain significance Arrhythmia 2019-02-17 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058429 SCV000089949 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:18752142;PMID:18752973). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000656174 SCV000678368 likely pathogenic Wolff-Parkinson-White pattern 2017-07-14 no assertion criteria provided research This variant was identified in an individual with Wolff-Parkinson-White syndrome

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