Submissions for variant NM_000335.5(SCN5A):c.2678G>A (p.Arg893His)

gnomAD frequency: 0.00001  dbSNP: rs199473172

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766747	SCV000617274	uncertain significance	not provided	2021-02-24	criteria provided, single submitter	clinical testing	Identified in several patients referred for Brugada syndrome genetic testing (Kapplinger et al., 2010), in patients with sudden unexplained death and suspected Brugada syndrome (Lin et al., 2017; Tadros et al., 2017), and in one individual with reported Brugada pattern on EKG referred for genetic testing at GeneDx; however, details confirming a clinical diagnosis of Brugada syndrome were not provided; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published in vitro cellular electrophysiology studies suggest this variant results in no detectable channel current in transfected HEK-293 cells; however, details of the functional analysis were not provided (Kapplinger et al., 2015); A missense variant in the same residue (R893C) has been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014); however, the pathogenicity of this variant has not been definitively determined; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#67749; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 23503384, 28341781, 24136861, 20129283, 25904541, 29247119, 30662450, 29759671, 30193851)
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000520411	SCV000747932	uncertain significance	not specified	2016-06-28	criteria provided, single submitter	clinical testing
Invitae	RCV000766747	SCV000832454	pathogenic	not provided	2022-11-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg893 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28341781; Invitae). 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: 25904541). 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. ClinVar contains an entry for this variant (Variation ID: 67749). This missense change has been observed in individuals with Brugada syndrome (PMID: 20129283, 20381179, 23503384, 28341781, 29247119; Invitae). This variant is present in population databases (rs199473172, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 893 of the SCN5A protein (p.Arg893His).
Ambry Genetics	RCV002426619	SCV002744675	likely pathogenic	Cardiovascular phenotype	2021-11-01	criteria provided, single submitter	clinical testing	The p.R893H variant (also known as c.2678G>A), located in coding exon 15 of the SCN5A gene, results from a G to A substitution at nucleotide position 2678. The arginine at codon 893 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in individuals with Brugada syndrome and sudden unexplained death as well as in unaffected individuals (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Doetzer AD et al. Int. J. Cardiol., 2011 Aug;150:e96-7; Zakliaz'minskaia EV et al. Khirurgiia (Mosk), 2013;:49-53; Wang D et al. Forensic Sci. Int., 2014 Apr;237:90-9; Lin Y et al. Circ Cardiovasc Genet, 2017 Dec;10; Yamagata K et al. Circulation, 2017 Jun;135:2255-2270; Tadros R et al. JACC Clin Electrophysiol, 2017 12;3:1400-1408; Chinushi M et al. Pacing Clin Electrophysiol, 2011 Jan;34:e1-5). In addition, functional studies show that this alteration produces abnormal electrophysiological effects in transfected HEK-293 cells (Kapplinger JD et al. Circ Cardiovasc Genet, 2015 Aug;8:582-95). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000058518	SCV004175238	likely pathogenic	Brugada syndrome	2023-07-19	criteria provided, single submitter	clinical testing	The SCN5A c.2678G>A variant is classified as Likely Pathogenic (PS3_Moderate, PS4_Moderate, PM1, PM2, PP3) The SCN5A c.2678G>A variant is a single nucleotide change in exon 16/28 of the SCN5A gene, which is predicted to change the amino acid arginine at position 893 in the protein, to histidine. The variant has been reported in greater than 6 probands with a clinical presentation of Brugada syndrome/SCD (PMID#25904541, 20129283, 29247119, 29759671, ClinVar)(PS4_Moderate) and is rare in population databases (gnomAD allele frequency = 0.00065%; 1 het and 0 hom) (PM2). Functional studies in HEK-293 cells show a deleterious effect of this variant with no current reported in a patch clamp assay, however, additional functional evidence is required to confirm the impact of this variant (PMID#25904541)(PS3_moderate). This variant is located in the functionally important DII S5/S6 transmembrane spanning region of the SCN5A protein (PM1) and computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs199473172), is reported as disease causing in the HGMD database (CM100679) and is reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar #67749).
All of Us Research Program, National Institutes of Health	RCV000058518	SCV004843399	pathogenic	Brugada syndrome	2023-11-10	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 893 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). This variant is found within a highly conserved region (a.a.718-938) at transmembrane domain DII. Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). A functional study has shown that this variant causes a loss-of-function phenotype with no detectable channel current in transfected HEK293 cells (PMID: 25904541). This variant has been reported in over ten unrelated individuals affected with Brugada syndrome (PMID: 19356768, 20381179, 23503384, 25904541 , 28341781, 29759671, 32298319, 32893267, 35052356, 36091819, 37061847, 37547970, ClinVar SCV000832454.4, doi:10.3329/cardio.v15i1.61916), in two individuals suspected of having Brugada syndrome (PMID: 20381179, ClinVar SCV000617274.1), and in another individual affected with sudden unexplained death (PMID: 29247119). This variant has been reported to be a de novo occurrence in one of the affected carriers without confirmation of paternity and maternity (PMID: 35052356). This variant has been identified in 1/250868 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV000058518	SCV005045292	likely pathogenic	Brugada syndrome	2024-05-24	criteria provided, single submitter	clinical testing	Heterozugous varint NM_198056.3:c.2678G>A (p.Arg893His) in the SNC5A gene was found in male proband (27 y.o., Caucasian) with spontaneous Brugada pattern, syncope, VT, ICD implanted (PMID: 36091819). Family history burdened with SCD before 40 years of age. This variant is in The Genome Aggregation Database (gnomAD) v4.1.0 with total MAF 0.000002478 (Date of access 23-05-2024). Most in silico predictors show pathogenic result of the protein change (varsome.com). In accordance with ACMG(2015) criteria and Enhanced rare variant interpretation in inherited arrhythmias (PMID: 32893267) this variant is classified as Likely Pathogenic with following criteria selected: PM1_Strong, PM2, PP3.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058518	SCV000090038	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.