Submissions for variant NM_000335.5(SCN5A):c.1126C>T (p.Arg376Cys)

dbSNP: rs199473100

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000058395	SCV000235588	likely pathogenic	not provided	2017-02-20	criteria provided, single submitter	clinical testing	The Arg376Cys variant was identified in three members of a family with sick sinus syndrome (Detta et al., 2014). Functional studies showed a significant reduction of the inward sodium current in heterologous cells that were expressing the Arg376Cys allele (Detta et al., 2014).The Arg376Cys variant results in a non-conservative amino acid substitution of a positively charged Arginine with an uncharged, polar Cysteine at a position that is conserved in mammals. This variant resides in the extracellular pore loop region between S5-S6 of DI. In silico analysis predicts Arg376Cys is damaging to the protein structure/function. While this allele has been observed in one out of 1300 control individuals (Kapa et al., 2009; Kapplinger et al., 2012), it was absent from individuals in both the NHLBI Exome Sequencing Project and the Exome Aggregation Consortium database, indicating it is not a common benign variant in these populations. Moreover, a missense pathogenic variant at the same residue (Arg376His) and in nearby residues (Met369Lys, Trp374Gly, Gly386Arg) have been reported in the Human Gene Mutation Database in association with Brugada syndrome (Stenson et al., 2014).Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000058395	SCV000760203	pathogenic	not provided	2023-09-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg376 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15851228, 16344400, 28341781). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SCN5A function (PMID: 24295898). 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 67638). This missense change has been observed in individuals with clinical features of Brugada syndrome and/or SCN5A-related conditions (PMID: 24295898, 34461752; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 376 of the SCN5A protein (p.Arg376Cys).
Mendelics	RCV000991042	SCV001142146	uncertain significance	Brugada syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000677	SCV001157709	likely pathogenic	not specified	2018-07-05	criteria provided, single submitter	clinical testing	The SCN5A c. 1126C>T; p. Arg376Cys variant (rs199473100) is reported in the literature in 1 family and 3 individuals, of which 2 were affected with sick sinus syndrome-1 (SSS1), and the third may not have yet manifested disease phenotypes (Detta 2014). Functional analyses in vitro demonstrate a significant reduction in sodium channel currents (Detta 2014), similar to analyses of other SCN5A variants associated with SSS1, and consistent with impaired excitability of cardiomyocytes leading to SSS1 (Gui 2010). This variant is reported as either likely pathogenic or of uncertain significance, each by 1 laboratory in ClinVar (Variation ID: 78534), and considered disease causing in HGMD. This variant is absent from most general population databases (1000 Genomes Project and Genome Aggregation Database), with a single individual in the Exome Variant Server, indicating it is not a common polymorphism. Additionally, other variants at this codon (c.1127G>A, p.Arg376His; c.1127G>T, p.Arg376Leu) have been reported in individuals with Brugada syndrome (Rossenbacker 2004) and sudden unexplained death (Christiansen 2016), respectively. The Arg376His variant is reported as pathogenic by 2 laboratories, and likely pathogenic by 1 laboratory in ClinVar (Variation ID: 78535). The Arg376Leu variant is not in ClinVar. The arginine at codon 376 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic.
Ambry Genetics	RCV004019030	SCV004943812	uncertain significance	Cardiovascular phenotype	2020-03-20	criteria provided, single submitter	clinical testing	The c.1126C>T (p.R376C) alteration is located in exon 9 (coding exon 8) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 1126, causing the arginine (R) at amino acid position 376 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058395	SCV000089915	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:19841300;PMID:20129283).