ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.1844G>A (p.Gly615Glu) (rs12720452)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000148853 SCV000055219 likely benign Long QT syndrome, drug-associated 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151792 SCV000200248 uncertain significance not specified 2019-02-11 criteria provided, single submitter clinical testing The p.Gly615Glu variant in SCN5A has been reported in at least 10 individuals with LQTS, 4 individuals with sudden death, 1 individual with Brugada syndrome, 1 individual with HCM and 1 individual with delayed enhancement in LV (Albert 2008, Beyder 2010, Itoh 2016, Kapplinger 2009, Le Scouarnec 2015, Lieve 2013, Methner 2016, Ng 2013, Paulussen 2004, Sanchez 2016, Tester 2005, Yang 2002). In vitro functional studies provide some evidence that the p.Gly615Glu variant may impact protein function (Beyder 2014, Albert 2008). However, these types of assays may not accurately represent biological function. This variant has also been reported in ClinVar (Variation ID 67691) and has been identified in 50/106156 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs12720452). Computational prediction tools and conservation analysis suggest that the p.Gly615Glu variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, due to conflicting data, the p.Gly615Glu variant is uncertain. ACMG/AMP Criteria applied: PS4, PP3, PS3_S, BS1 (Richards 2015).
Invitae RCV000168217 SCV000218883 uncertain significance Brugada syndrome 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 615 of the SCN5A protein (p.Gly615Glu). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs12720452, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals tested for long QT syndrome (PMID: 15840476, 19716085, 23631430), drug induced long QT syndrome (PMID: 11997281), irritable bowel syndrome (PMID: 24613995), and Brugada syndrome (PMID: 20129283) and in an individual who suffered sudden infant death (PMID: 30079003). ClinVar contains an entry for this variant (Variation ID: 67691). This variant has been reported to have conflicting or insufficient data to determine the effect on SCN5A protein function (PMID: 11997281, 24613995, 31262209). 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.
GeneDx RCV000766786 SCV000235386 uncertain significance not provided 2018-12-13 criteria provided, single submitter clinical testing The G615E variant of uncertain significance in the SCN5A gene has been reported in several patients referred for LQTS genetic testing (Kapplinger et al., 2009). This variant has also been reported in one individual with Brugada syndrome; however, this individual also harbored a second variant in the SCN5A gene that was deemed deleterious (Le Scouarnec et al., 2015). The G615E varinat has been identified in several individuals who developed torsades de pointe after exposure to a QT-prolonging drug (Yang et al., 2002; Ramirez et al., 2013). Furthermore, the G615E variant has been identified via postmortem genetic testing in association with unexplained deaths (Albert et al., 2008; Methner et al., 2016; Sanchez et al., 2016; Munroe et al., 2018). This variant has been observed at GeneDx in several unrelated individuals referred for arrhythmia and cardiomyopathy genetic testing. The G615E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and it occurs at a position that is conserved in mammals. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. In addition, in vitro functional analyses of this variant have been discordant regarding the existence of a significant effect on sodium channel function (Yang et al., 2002; Albert et al., 2008; Beyder et al., 2014). Finally, G615E was observed in 60/224294 (0.03%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000521151 SCV000616621 uncertain significance Long QT syndrome 3 2017-04-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000622256 SCV000737801 uncertain significance Cardiovascular phenotype 2020-06-10 criteria provided, single submitter clinical testing The p.G615E variant (also known as c.1844G>A), located in coding exon 11 of the SCN5A gene, results from a G to A substitution at nucleotide position 1844. The glycine at codon 615 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in subjects with acquired long QT syndrome, long QT syndrome and Brugada syndrome (Yang P et al. Circulation, 2002 Apr;105:1943-8; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Le Scouarnec S et al. Hum. Mol. Genet., 2015 May;24:2757-63). It has also been reported in sudden death and stillbirth cohorts (Albert CM et al. Circulation, 2008 Jan;117:16-23; Methner DN et al. Genome Res., 2016 Sep;26:1170-7; Munroe PB et al. Circ Genom Precis Med, 2018 01;11:e001817). This variant has also been seen in exome cohorts, as well as an irritable bowel syndrome cohort (Dorschner MO et al. Am J Hum Genet. 2013;93(4):631-40; Beyder A et al. Gastroenterology, 2014 Jun;146:1659-68; Amendola LM et al. Genome Res. 2015;25(3):305-15; Maxwell KN et al. Am. J. Hum. Genet., 2016 May;98:801-17). Functional studies have shown little or no impact on voltage function, but possible mechanosensitivity effects; however, the clinical relevance of these findings is uncertain (Yang P et al. Circulation, 2002 Apr;105:1943-8; Albert CM et al. Circulation, 2008 Jan;117:16-23; Strege PR et al. Channels (Austin), 2019 12;13:287-298). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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 RCV000151792 SCV000920188 uncertain significance not specified 2021-08-16 criteria provided, single submitter clinical testing Variant summary: SCN5A c.1844G>A (p.Gly615Glu) results in a non-conservative amino acid change located in the Voltage-gated Na+ ion channel, cytoplasmic domain of 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 0.00028 in 199960 control chromosomes. The observed variant frequency is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Long QT Syndrome With Sudden Cardiac Death phenotype (2.1e-05), strongly suggesting that the variant is benign. c.1844G>A has been reported in the literature in multiple LQTS patients, including some diagnosed with Sudden Cardiac Death and LQTS triggered by quinidine (e.g. Lieve_2013, Sanchez_2016, Methner_2016, Anderson_2017, Marschall_2019). In addition, this variant was also reported in one proband with neonatal DCM, one family member with episode of chest pain with normal QT interval, and three aymptomatic family members with prolonged QT interval (Hawley_2020). These data do not provide unequivocal conclusions about association of the variant with LQTS or other diseases. Functional studies have reported conflicting results with no effect on the peak amplitude of voltage-gated sodium current (Yang_2002), positive shifts in voltage dependence of activation, with altered activation kinetics and slower activation than wildtype associated with this variant (Beyder_2014), and disruptions in mechanosensitivity (Strege_2019). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Pathogenic n=2, VUS n=8). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000766786 SCV001153875 uncertain significance not provided 2017-01-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV001189146 SCV001356371 uncertain significance Arrhythmia 2021-02-17 criteria provided, single submitter clinical testing This missense variant replaces glycine with glutamic acid at codon 615 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 may alter sodium channel activation and inactivation kinetics (PMID: 18071069, 24613995) Additionally, one functional study has shown that the mutant channel affects mechanosensitivity of voltage-dependent gating compared to the wild type channel (PMID: 31262209). This variant has been reported in individuals affected with Brugada syndrome (PMID: 20129283), irritable bowel syndrome (PMID: 24613995) and sudden cardiac death (PMID: 18071069). This variant has been reported in an individual affected with long QT syndrome, who also carried a pathogenic variant in the KCNQ1 gene (PMID: 23631430) and in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 32553227). This variant has also been reported in one individual affected with neonatal dilated cardiomyopathy and three individuals with prolonged QT intervals in one family (PMID: 32516855). This variant has been identified in 66/227496 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000766786 SCV001714693 uncertain significance not provided 2020-03-12 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058455 SCV000089975 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:14760488;PMID:15840476;PMID:19716085;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington RCV000148853 SCV000190597 uncertain significance Long QT syndrome, drug-associated 2014-06-01 no assertion criteria provided research
Forensic Genetics Laboratory,Harris County Institute of Forensic Sciences RCV000234973 SCV000263112 pathogenic Death in infancy 2015-03-27 no assertion criteria provided clinical testing
Forensic Genetics Laboratory,Harris County Institute of Forensic Sciences RCV000234978 SCV000263121 pathogenic Death in early adulthood 2015-03-28 no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000766786 SCV001919947 uncertain significance not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000766786 SCV001930168 uncertain significance not provided no assertion criteria provided clinical testing

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