Submissions for variant NM_000335.5(SCN5A):c.4293G>C (p.Arg1431Ser)

dbSNP: rs199473246

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414661	SCV000491130	uncertain significance	not provided	2018-09-10	criteria provided, single submitter	clinical testing	The R1432S variant of uncertain significance has been identified in the SCN5A gene. This variant has been reported in patients referred for genetic testing for Brugada syndrome and LQTS (Kapplinger et al., 2009; Kapplinger et al., 2010); however, additional clinical and segregation information was not provided. In one study, Proost et al. (2017) identified this variant in one individual suspected to have Brugada syndrome, however, a second missense variant in the DSP gene was also identified in this family and segregation studies were reported as inconclusive. Nevertheless, the R1432S variant is not observed in large population cohorts (Lek et al., 2016). Additionally, the R1432S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs in the S5-S6 extracellular loop that constitutes the pore region of NaV1.5. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Functional studies demonstrated that the R1432G mutant protein was retained inside the endoplasmic reticulum, indicating that the absence of a positively charged residue at position R1432 results in a loss of sodium channel function (Baroudi et al., 2001), further supporting the functional importance of this positively charged R1432 residue. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Color Diagnostics, LLC DBA Color Health	RCV001842360	SCV001357585	uncertain significance	Cardiac arrhythmia	2019-09-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with serine at codon 1432 of the SCN5A protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ≥0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual referred for long QT syndrome genetic test (PMID: 19716085). This variant has not been identified 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	RCV001842360	SCV004835347	uncertain significance	Cardiac arrhythmia	2023-11-30	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058658	SCV000090178	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:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.