Submissions for variant NM_000335.5(SCN5A):c.2066G>A (p.Arg689His)

gnomAD frequency: 0.00009  dbSNP: rs199473145

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000148852	SCV000055301	uncertain significance	Long QT syndrome	2018-04-05	criteria provided, single submitter	research
GeneDx	RCV000058477	SCV000235399	uncertain significance	not provided	2024-01-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15851227, 19841300, 21321465, 28988457, 29728395, 31043699, 31315195, 24055113, 23465283, 22378279, 25637381, 15996170, 16453024, 26746457, 28341781, 20129283, 27871843, 23692053, 22490985, 34219138, 33232181, 33131149, 35932045, 16414944, 30847666)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212991	SCV000272409	uncertain significance	not specified	2015-08-03	criteria provided, single submitter	clinical testing	The p.Arg689His variant in SCN5A has been previously reported in 6 individuals w ith arrhythmia (3 with Brugada syndrome, 1 with long QT, 1 with VT and mitral va lvular disease, and 1 with progressive conduction disease and episodes of syncop e; Maekawa 2005, Napolitano 2005, Nakajima 2011, Hong 2012, Sottas 2013). In the family with episodes of syncope, the variant segregated with disease in 2 affec ted siblings who had syncope and sudden death and 2 additional family members wi th borderline QT prolongation (Sottas 2013). However, this variant has also been reported in 7/16128 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199473145). In vitro functional studies provide some evidence that the p.Arg689His variant may impact protein fu nction (Hong 2012, Sottas 2013), but these types of assays may not accurately re present biological function. Furthermore, arginine (Arg) at position 689 is not conserved in mammals or evolutionarily distant species, and 7 mammals carry a hi stidine (His) at this position, suggesting that this change may be tolerated. In summary, the clinical significance of the p.Arg689His variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000058477	SCV000545033	uncertain significance	not provided	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 689 of the SCN5A protein (p.Arg689His). This variant is present in population databases (rs199473145, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 15996170, 16453024, 21321465, 23692053, 28341781, 33131149, 33232181, 37652022). ClinVar contains an entry for this variant (Variation ID: 67710). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 22490985, 23692053, 34219138). 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.
Ambry Genetics	RCV000617789	SCV000738162	uncertain significance	Cardiovascular phenotype	2024-04-27	criteria provided, single submitter	clinical testing	The p.R689H variant (also known as c.2066G>A), located in coding exon 13 of the SCN5A gene, results from a G to A substitution at nucleotide position 2066. The arginine at codon 689 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in individuals with Brugada syndrome, long QT syndrome, and other arrhythmias (Maekawa K et al. Ann. Hum. Genet., 2005 Jul;69:413-28; Napolitano C et al. JAMA, 2005 Dec;294:2975-80; Nakajima T et al. Int Heart J, 2011;52:27-31; Hong K et al. Eur. J. Hum. Genet., 2012 Nov;20:1189-92). In addition, this variant was reported in twins with sudden cardiac death, a sibling with progressive cardiac conduction disease, and two reportedly asymptomatic relatives (Sottas V et al. J. Cardiovasc. Electrophysiol., 2013 Sep;24:1037-46). In multiple assays testing SCN5A function, this variant showed functionally normal and functionally abnormal results (Sottas V et al. J. Cardiovasc. Electrophysiol., 2013 Sep;24:1037-46; Hong K et al. Eur. J. Hum. Genet., 2012 Nov;20:1189-92). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the available evidence, the clinical significance of this variant remains unclear.
Illumina Laboratory Services, Illumina	RCV000779408	SCV000916020	uncertain significance	SCN5A-Related Arrhythmias	2019-01-07	criteria provided, single submitter	clinical testing	Several studies have reported patients with arrhythmias who are heterozygous for the SCN5A c.2066G>A (p.Arg689His) missense variant (Maekawa et al., 2005; Napolitano et al., 2005; Nakajima et al., 2011; Hong et al., 2012). Additionally, a three-generation family was reported by Sottas et al. (2013) in which two twin girls suffered sudden cardiac death from their first syncope at ages four and five. Their sister had her first syncope at five months and has a pacemaker. All three sisters are heterozygous for the p.Arg689His variant, as are their mother and maternal grandmother, who have prolonged QT intervals on ECG. The p.Arg689His variant has been found in three of 1,276 healthy controls and is reported at a frequency of 0.000434 in the South Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg689His variant is classified as a variant of unknown significance but suspicious for pathogenicity for SCN5A-related arrhythmias. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Mendelics	RCV000987218	SCV001136467	uncertain significance	Brugada syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842308	SCV001350180	uncertain significance	Cardiac arrhythmia	2023-12-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 689 of the SCN5A protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Experimental functional studies have provided contradicting results regarding the impact of this variant on the sodium channel function. One study has suggested that the mutant protein carrying this variant is unable to generate current in transfected cells (PMID: 22490985), while a different study has suggested that most of the channel properties of the mutant protein were similar to the wild type protein (PMID: 23692053). This variant has been reported in individuals affected with Brugada syndrome (PMID: 21321465, 28341781), Brugada-like phenotype (PMID: 22490985), arrhythmia (PMID: 15996170, 23692053), sudden infant death syndrome (PMID: 16453024), sudden cardiac death (PMID: 23692053), and dilated cardiomyopathy (PMID: 37461109). This variant has also been identified in 23/248792 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.
Fulgent Genetics, Fulgent Genetics	RCV002490653	SCV002789990	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	2021-10-13	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000058477	SCV003821341	uncertain significance	not provided	2022-01-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001842308	SCV004823405	uncertain significance	Cardiac arrhythmia	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 689 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). Experimental functional studies have provided contradicting results regarding the impact of this variant on the sodium channel function. One study has suggested that the mutant protein carrying this variant is unable to generate current in transfected cells (PMID: 22490985), while a different study has suggested that most of the channel properties of the mutant protein were similar to the wild type protein (PMID: 23692053). This variant has been reported in individuals affected with Brugada syndrome (PMID: 21321465, 28341781), Brugada-like phenotype (PMID: 22490985), arrhythmia (PMID: 15996170, 23692053), sudden infant death syndrome (PMID: 16453024), and sudden cardiac death (PMID: 23692053). This variant has also been identified in 23/248792 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	RCV000058477	SCV000089997	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:15851227;PMID:16414944;PMID:19841300;PMID:21321465;PMID:20129283;PMID:22378279).
CSER _CC_NCGL, University of Washington	RCV000148852	SCV000190596	uncertain significance	Long QT syndrome	2014-06-01	no assertion criteria provided	research