ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1844G>A (p.Gly615Glu) (rs12720452)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000622256 SCV000737801 uncertain significance Cardiovascular phenotype 2018-02-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Biesecker Lab/Human Development Section,National Institutes of Health RCV000148853 SCV000055219 likely benign Long QT syndrome, drug-associated 2013-06-24 criteria provided, single submitter research
CSER_CC_NCGL; University of Washington Medical Center RCV000148853 SCV000190597 uncertain significance Long QT syndrome, drug-associated 2014-06-01 no assertion criteria provided research
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.
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
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
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.
Integrated Genetics/Laboratory Corporation of America RCV000151792 SCV000920188 uncertain significance not specified 2017-09-11 criteria provided, single submitter clinical testing Variant summary: The SCN5A c.1844G>A (p.Gly615Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies have reported conflicting results with no effect on the peak amplitude of voltage-gated sodium current (Yang_2002) versus positive shifts in voltage dependence of activation, with altered activation kinetics and slower activation than wildtype associated with this variant (Beyder_2014). The variant was found in the control population dataset of ExAC in 25/108674 control chromosomes at a frequency of 0.00023, which is approximately 11 times the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0000208), suggesting this variant is likely a benign polymorphism. Different clinical diagnostic laboratories/reputable databases have conflicting classifications for this variant (uncertain significance, pathogenic, likely benign). The variant of interest has been reported in multiple LQTS patients, including some diagnosed with Sudden Cardiac Death and LQTS triggered by quinidine (Sanchez_2016, Methner_2016, Lieve_2013). However, evidence for an unequivocal classification of Long-QT or Brugada syndrome was not indicated in these studies. Considering the conflicting evidence of functional implication of this variant and reports of its presence in patients with with LQTS/SIDS/Brugada-like "without" evidence for co-seggregation versus a high prevalence in control databases such as ExAc and gnomAD, this variant is classified as a VUS-possibly normal until more definitive studies become available.
Invitae RCV000168217 SCV000218883 uncertain significance Brugada syndrome 2018-11-30 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). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "tolerated"; PolyPhen-2: "probably damaging”; Align-GVGD: "Class C0"). While some experimental studies have shown that this missense change does not significantly alter sodium channel activity (PMID: 11997281, 18071069), other studies found a decrease in peak current and a shift in voltage dependent activation (PMID: 24613995). The clinical significance of these conflicting observations is uncertain. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151792 SCV000200248 uncertain significance not specified 2018-11-26 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Gly615Glu var iant in SCN5A has been reported in at least 10 individuals with LQTS, 4 individ uals with sudden death, 1 individual with Brugada syndrome, 2 individuals with H CM and 1 individual with delayed enhancement in LV (Albert 2008, Beyder 2010, It oh 2016, Kapplinger 2009, Le Scouarnec 2015, Lieve 2013, Methner 2016, Ng 2013, Paulussen 2004, Sanchez 2016, Tester 2005, Yang 2002, LMM data). In vitro functi onal studies are conflicting as to whether this variant impacts protein function (Yang 2002, Albert 2008, Beyder 2014, Anderson 2017). This variant has also bee n reported by other clinical laboratories in ClinVar (Variation ID 67691) and ha s been identified in 0.05% (56/108146) European chromosomes by gnomAD (http://gn omad.broadinstitute.org). Computational prediction tools and conservation analys is do not provide strong support for or against an impact to the protein. In sum mary, due to conflicting data, the clinical significance of the p.Gly615Glu vari ant is uncertain, however, its frequency suggests that it is more likely to be b enign. ACMG/AMP Criteria applied: BS1_Supporting, PS4.

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