Submissions for variant NM_000335.5(SCN5A):c.1567C>T (p.Arg523Cys)

gnomAD frequency: 0.00001  dbSNP: rs199473119

Total submissions: 7

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; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; Atrial fibrillation, familial, 10	2012-12-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000239767	SCV000545031	uncertain significance	not provided	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 523 of the SCN5A protein (p.Arg523Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 18752142, 32233023, 35397174). ClinVar contains an entry for this variant (Variation ID: 67667). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects SCN5A function (PMID: 35397174). 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 Diagnostics, LLC DBA Color Health	RCV001842283	SCV001340217	uncertain significance	Cardiac arrhythmia	2021-02-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 523 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual referred for long QT syndrome genetic testing (PMID: 18752142) and in an individual affected with sudden death in epilepsy (PMID: 18752973) and in an individual affected with Wolff–Parkinson–White syndrome (PMID: 32233023). This variant has been identified in 2/239130 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV001842283	SCV004821411	uncertain significance	Cardiac arrhythmia	2023-11-30	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