Submissions for variant NM_000335.5(SCN5A):c.2236G>A (p.Glu746Lys)

gnomAD frequency: 0.00001  dbSNP: rs199473582

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV004700365	SCV000589535	uncertain significance	not provided	2024-08-13	criteria provided, single submitter	clinical testing	Identified in association with Brugada syndrome and LQTS in published literature (PMID: 20129283, 30193851, 37547970); Identified in a patient with ARVC who also exhibited provocable coved-type ST-segment elevation in right precordial leads on ECG (PMID: 18304999); Published functional studies suggest a significantly reduced current density compared to wildtype (PMID: 32533946); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26332594, 22956155, 34426522, 30662450, 30193851, 20129283, 32533946, 18304999, 30203441, 37547970)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000058489	SCV000954490	uncertain significance	Brugada syndrome	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 746 of the SCN5A protein (p.Glu746Lys). This variant is present in population databases (rs199473582, gnomAD 0.008%). This missense change has been observed in individuals with clinical features of SCN5A-related conditions (PMID: 18304999, 20129283, 30193851; Invitae). ClinVar contains an entry for this variant (Variation ID: 67721). 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 tolerated. Experimental studies have shown that this missense change affects SCN5A function (PMID: 32533946). 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.
Mendelics	RCV000987216	SCV001136465	uncertain significance	Brugada syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498341	SCV002776550	uncertain significance	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2021-11-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298120	SCV003997039	uncertain significance	Cardiovascular phenotype	2023-05-08	criteria provided, single submitter	clinical testing	The p.E746K variant (also known as c.2236G>A), located in coding exon 13 of the SCN5A gene, results from a G to A substitution at nucleotide position 2236. The glutamic acid at codon 746 is replaced by lysine, an amino acid with similar properties. In one study, this variant was detected in an individual with features suggestive of arrhythmogenic right ventricular cardiomyopathy (ARVC) and Brugada syndrome (BrS) in whom ARVC gene analysis was limited (Peters S. Europace, 2008 Jul;10:816-20). This variant has also been detected in BrS cohorts; however, clinical details were limited and some case reports may overlap (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Berthome P et al. Heart Rhythm, 2019 Feb;16:260-267; Campuzano O et al. EBioMedicine, 2020 Apr;54:102732; Glazer AM et al. Am J Hum Genet, 2020 Jul;107:111-123; Walsh R et al. Genet Med, 2021 Jan;23:47-58). One in vitro study indicated this variant may impact protein function; however, additional evidence is needed to confirm this finding (Glazer AM et al. Am J Hum Genet, 2020 Jul;107:111-123). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000498105	SCV004222998	uncertain significance	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.2236G>A (p.Glu746Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 248406 control chromosomes (gnomAD). c.2236G>A has been reported in the literature in individuals affected with Brugada Syndrome or cardiomyopathy without strong evidence of causality (Peters_2008, Kapplinger_2010, Berthome_2019). These reports do not provide unequivocal conclusions about association of the variant with Brugada Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function, finding that it disrupts normal activity (Glazer_2020). The following publications have been ascertained in the context of this evaluation (PMID: 18304999, 20129283, 30193851, 32533946). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV003591667	SCV004361690	uncertain significance	Cardiac arrhythmia	2023-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 746 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant causes a partial reduction in peak current density in cultured cells (PMID: 32533946, O'Neill et al. 2021, DOI: 10.1101/2021.09.22.461398). This variant has been reported in at least five unrelated individuals affected with Brugada syndrome (PMID: 20129283, 32268277, 32893267). This variant has also been reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 18304999) or inherited heart diseases (O'Neill et al. 2021, DOI:10.4081/cardiogenetics.2013.e5), and in an individual suspected of having inherited arrhythmia syndrome (PMID: 22956155). This variant has been identified in 6/279818 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	RCV003591667	SCV004816695	uncertain significance	Cardiac arrhythmia	2024-03-05	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 746 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant causes a partial reduction in peak current density in cultured cells (PMID: 32533946, O'Neill et al. 2021, DOI: 10.1101/2021.09.22.461398). This variant has been reported in at least five unrelated individuals affected with Brugada syndrome (PMID: 20129283, 32268277, 32893267). This variant has also been reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 18304999) or inherited heart diseases (O'Neill et al. 2021, DOI:10.4081/cardiogenetics.2013.e5), and in an individual suspected of having inherited arrhythmia syndrome (PMID: 22956155). This variant has been identified in 6/279818 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058489	SCV000090009	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.