ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.3908C>T (p.Thr1303Met) (rs199473603)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618218 SCV000736754 uncertain significance Cardiovascular phenotype 2018-03-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Good segregation with disease (lod 1.5-3 = 5-9 meioses)
CSER_CC_NCGL; University of Washington Medical Center RCV000148846 SCV000190588 likely pathogenic Long QT syndrome 2014-06-01 no assertion criteria provided research
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058613 SCV000090133 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:10508990;PMID:10961955;PMID:17210839;PMID:19716085;PMID:19841300;PMID:17210841;PMID:22378279;PMID:22685113). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000470787 SCV000805033 likely pathogenic Brugada syndrome 2017-01-13 no assertion criteria provided clinical testing
Color RCV000777742 SCV000913703 uncertain significance Arrhythmia 2018-10-18 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the transmembrane domain of the SCN5A protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental studies have shown inconsistent results with regard to the impact of this variant on the SCN5A ion channel function (PMID: 17210841, 18451998). This variant has been reported in unrelated individuals affected with long QT syndrome (PMID: 19841300), early-onset lone atrial fibrillation (PMID: 22685113, 24144883) and sudden unexplained death (PMID: 17210839, 17210841, 24631775). This variant has been reported to segregate with long QT syndrome in multiple members of a family (PMID: 10508990). This variant has also been reported in a small family with Brugada syndrome (PMID: 25210526). In addition, this variant has been identified in 42/275748 chromosomes (35/126116 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Due to the conflicting functional study results and occurrence in the general population, available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Donald Williams Parsons Laboratory,Baylor College of Medicine RCV000496069 SCV000599943 pathogenic Long QT syndrome 3 2013-09-13 no assertion criteria provided research This variant has been previously reported as disease-causing. It was an incidental finding in our study, maternally inherited in a 8-year-old male with medulloblastoma.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725469 SCV000337160 uncertain significance not provided 2015-11-16 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000496069 SCV000883131 likely pathogenic Long QT syndrome 3 2018-11-21 criteria provided, single submitter clinical testing
GeneDx RCV000725469 SCV000235458 uncertain significance not provided 2018-04-24 criteria provided, single submitter clinical testing The T1304M variant of uncertain significance in the SCN5A gene has been published previously in several unrelated patients with LQTS and Brugada syndrome (Wattanasirichaigoon et al., 1999; Splawski et al., 2000; Arnestad et al., 2007; Kapplinger et al., 2009; Kim et al., 2013). However, LQTS is caused by gain of function variants in the SCN5A channel (NaV1.5), while Brugada syndrome is caused by loss of function variants. As this variant has been identified in individuals with diseases that have different mechanisms of pathogenicity, its clinical significance is uncertain. Additionally, functional studies by Wang et al. (2007) and Beyder et al. (2014) show conflicting results. This variant is observed in 19/60,672 (0.03%) individuals of European (Non-Finnish) ancestry in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016; Exome Variant Server). Nevertheless, the T1304M 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 this substitution occurs at a position that is conserved across species. Furthermore, the T1304M variant is located in the voltage sensor S4 helix.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000496069 SCV000584112 likely pathogenic Long QT syndrome 3 2015-11-12 criteria provided, single submitter research
Invitae RCV000470787 SCV000545009 uncertain significance Brugada syndrome 2018-11-06 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1304 of the SCN5A protein (p.Thr1304Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs199473603, ExAC 0.03%). This variant has been reported in the literature segregating with long QT syndrome (LQTS) in one small family (PMID: 10508990). In addition, it has been reported in unrelated individuals affected with LQTS (PMID: 19841300, 17210839), individuals of sudden infant unexplained death (PMID: 17210841, 24631775), individuals with atrial fibrillation (PMID: 22685113, 24144883), one family with Brugada syndrome (PMID: 25210526), as well as in individuals referred for LQTS genetic testing or for primary electrical disease testing (PMID: 19716085, 28341588). ClinVar contains an entry for this variant (Variation ID: 67835). One experimental study has shown that this missense change increased persistent sodium current in vitro (PMID: 17210841). However, another experimental study showed no effect when treated with flecainidine (PMID: 18451998). 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 RCV000824759 SCV000710929 uncertain significance not specified 2018-04-26 criteria provided, single submitter clinical testing The p.Thr1304Met variant in SCN5A has been reported in 3 individuals with long Q T syndrome, 1 infant with sudden infant death syndrome, 1 individual with Brugad a syndrome, 1 individual with early-onset atrial fibrillation (Wattanasirichaigo on 1999, Priori 2000, Splawski 2000, Arnestad 2007, Olesen 2012, Kim 2014). This variant segregated with LQTS in 2 affected relatives from 1 family and with Br ugada syndrome in 1 affected relative from 1 family. However, other clinical lab oratories have observed this variant in individuals who carried other disease-ca using variants (GeneDx, Emory, Invitae; personal communication) and this variant has been reported in multiple healthy individuals (Weeke 2015, Kapplinger 2015) . Additionally, it is unclear if the same variant would be causative for such a diverse set of phenotypes, suggesting that it may not have a functional effect. This variant has also been identified in 0.03% (35/126116) of European chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199473603). Additionally, in vitro functional studies have shown confli cting results (Want 2007, Makita 2008, Beyder 2014). In summary, due to the pres ence of conflicting data, the clinical significance of the p.Thr1304Met variant is uncertain. ACMG/AMP Criteria applied: PP1; BP5.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000725469 SCV000924952 uncertain significance not provided 2017-03-31 no assertion criteria provided provider interpretation

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