ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.3908C>T (p.Thr1303Met) (rs199473603)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725469 SCV000337160 uncertain significance not provided 2015-11-16 criteria provided, single submitter clinical testing
Invitae RCV000470787 SCV000545009 uncertain significance Brugada syndrome 2019-12-11 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%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in the literature segregating with long QT syndrome (LQTS) in a 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), a 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). This variant has been reported to affect SCN5A protein function (PMID: 17210841). 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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000496069 SCV000584112 likely pathogenic Long QT syndrome 3 2015-11-12 criteria provided, single submitter research
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,; 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.
Ambry Genetics RCV000618218 SCV000736754 uncertain significance Cardiovascular phenotype 2019-02-26 criteria provided, single submitter clinical testing Conflicting evidence
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
Color RCV000777742 SCV000913703 uncertain significance Arrhythmia 2020-03-04 criteria provided, single submitter clinical testing
Mendelics RCV000987206 SCV001136455 uncertain significance Brugada syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
Robert's Program,Boston Children's Hospital RCV000993797 SCV001146678 uncertain significance Conduction disorder of the heart 2020-01-17 criteria provided, single submitter research This variant is classified as a Variant of Uncertain Significance based on the following ACMG/AMP criteria: BS2, PP3, and PS3. Published functional in vitro and in vivio evidence (Wang et al 2007, Anderson et al 2017) supports this variant having an effect on the SCN5A protein, but population frequency (MAF of 0.0003 in non-finnish Europeans) is high compared to frequency of disease.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000824759 SCV001160606 uncertain significance not specified 2019-06-11 criteria provided, single submitter clinical testing The SCN5A c.3911C>T; p.Thr1304Met variant (rs199473603) is reported in the literature in individuals affected with long-QT syndrome (Kapa 2009, Wattanasirichaigoon 1999), Brugada syndrome (Kim 2014), which have different mechanisms of pathogenicity. This variant is also reported with conflicting interpretations by multiple laboratories in ClinVar (Variation ID: 67835), and is found in the non-Finnish European population with an allele frequency of 0.031% (40/127748 alleles) in the Genome Aggregation Database. The threonine at codon 1304 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, functional analyses of the variant protein show conflicting effects on channel function (Beyder 2014, Wang 2007). Due to conflicting information, the clinical significance of the p.Thr1304Met variant is uncertain at this time. References: Beyder A et al. Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome. Gastroenterology. 2014 Jun;146(7):1659-1668. Kapa S et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 Nov 3;120(18):1752-60. Kim G et al. A pediatric case of Brugada syndrome diagnosed by fever-provoked ventricular tachycardia. Korean J Pediatr. 2014 Aug;57(8):374-8. Wang DW et al. Cardiac sodium channel dysfunction in sudden infant death syndrome. Circulation. 2007 Jan 23;115(3):368-76. Wattanasirichaigoon D et al. Sodium channel abnormalities are infrequent in patients with long QT syndrome: identification of two novel SCN5A mutations. Am J Med Genet. 1999 Oct 29;86(5):470-6.
Illumina Clinical Services Laboratory,Illumina RCV001147536 SCV001308365 benign Sick sinus syndrome 1, autosomal recessive 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Johns Hopkins Genomics,Johns Hopkins University RCV000987206 SCV001425372 uncertain significance Brugada syndrome 1 2020-05-14 criteria provided, single submitter clinical testing
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.
CSER _CC_NCGL, University of Washington RCV000148846 SCV000190588 likely pathogenic Long QT syndrome 2014-06-01 no assertion criteria provided research
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.
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
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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