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

gnomAD frequency: 0.00021  dbSNP: rs199473603

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000725469	SCV000235458	uncertain significance	not provided	2024-02-22	criteria provided, single submitter	clinical testing	Reported in individuals with various cardiac phenotypes, including LQTS, Brugada syndrome, lone atrial fibrillation, sudden infant death syndrome, cardiomyopathy, and T-wave inversion (PMID: 17210839, 10508990, 10973849, 19716085, 22685113, 25210526, 23465283, 29764897, 31514951, 34065239); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies have been reported and show conflicting results (PMID: 17210841, 24613995); This variant is associated with the following publications: (PMID: 10973849, 19716085, 28316956, 31514951, 30193851, 22685113, 23465283, 22378279, 25637381, 25210526, 10961955, 18503232, 23272275, 24055113, 24613995, 25351510, 25410959, 25904541, 25898860, 27153395, 29247119, 28412158, 28341588, 30677491, 28988457, 31019283, 31043699, 32048431, 30291343, 30847666, 29764897, 26743238, 19841300, 24144883, 24631775, 26746457, 31395126, 34426522, 34065239, 34621001, 34461752, 33772059, 35060774, 30203441, 10508990, 17210839, 29790872, 17210841)
Eurofins Ntd Llc (ga)	RCV000725469	SCV000337160	uncertain significance	not provided	2015-11-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000725469	SCV000545009	uncertain significance	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1304 of the SCN5A protein (p.Thr1304Met). This variant is present in population databases (rs199473603, gnomAD 0.03%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 10508990, 17210839, 17210841, 19716085, 19841300, 24631775, 25210526, 28341588, 30847666). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67835). 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 disruptive. Experimental studies have shown that this missense change affects SCN5A 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	uncertain significance	Long QT syndrome 3	2024-01-04	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham 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.
Ambry Genetics	RCV000618218	SCV000736754	uncertain significance	Cardiovascular phenotype	2024-01-04	criteria provided, single submitter	clinical testing	The c.3911C>T (p.T1304M) alteration is located in exon 22 (coding exon 21) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 3911, causing the threonine (T) at amino acid position 1304 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of 0.017% (46/279030) total alleles studied. The highest observed frequency was 0.031% (40/127748) of European (non-Finnish) alleles. This alteration has been reported in association with long QT syndrome (Wattanasirichaigoon, 1999; Kapplinger, 2009). In one family, alteration carriers showed variable clinical and electrophysiological phenotypes with several having borderline findings (Wattanasirichaigoon, 1999). This alteration was also detected in individuals with a transient Brugada pattern, lone atrial fibrillation, or sudden infant death syndrome (Wang, 2007; Olesen, 2012; Wang, 2014; Kim, 2014). In addition, this alteration was reported in hypertrophic cardiomyopathy, dilated cardiomyopathy cohorts as well as exome sequencing and cohorts not selected for the presence of cardiovascular disease; however, limited clinical information was provided (Andreasen, 2013; Dorschner, 2013; Lopes, 2015; Amendola, 2015; Van Driest, 2016; Gigli, 2019; Diebold, 2020). This amino acid position is highly conserved in available vertebrate species. While some research groups reported that this alteration would lead to gain of function effects (Wang, 2007; Arnestad, 2007), others found no significant difference between mutant and wild type channel function (Makita, 2008; Beyder, 2014); however, the experimental systems were not the same and the physiological significance of these results is unclear. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001842354	SCV000913703	uncertain significance	Cardiac arrhythmia	2023-12-04	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 1304 of the SCN5A protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown inconsistent results regarding the impact of this variant on the SCN5A ion channel function (PMID: 17210841, 18451998). This variant has been reported in individuals affected with long QT syndrome (PMID: 19841300), early-onset lone atrial fibrillation (PMID: 22685113, 24144883), sudden unexplained death (PMID: 17210839, 17210841, 24631775, 32652122), and dilated cardiomyopathy (PMID: 36129056). This variant has been reported to segregate with long QT syndrome in multiple members of a family (PMID: 10508990). This variant has been reported in a small family with Brugada syndrome (PMID: 25210526). This variant has also been identified in 46/279030 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to the conflicting functional study results and appreciable allele frequency in the general population, the role of this variant in disease cannot be determined conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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	RCV000725469	SCV001160606	uncertain significance	not provided	2020-02-18	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) or 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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000987206	SCV001425372	uncertain significance	Brugada syndrome 1	2020-05-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000987206	SCV001527656	uncertain significance	Brugada syndrome 1	2018-04-20	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
CeGaT Center for Human Genetics Tuebingen	RCV000725469	SCV005050815	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing	SCN5A: PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000824759	SCV005185790	uncertain significance	not specified	2024-05-15	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.3911C>T (p.Thr1304Met) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 247644 control chromosomes. The observed variant frequency is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Long QT Syndrome phenotype (2.1e-05), strongly suggesting that the variant is benign. c.3911C>T has been reported in the literature in individuals affected with Long QT Syndrome and other related conditions (e.g. Wattanasirichaigoon_1999, Arnestad_2007, Kapplinger_2009, Kapa_2009, van Lint_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and demonstrates an affect on protein function (Wang_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17210839, 19841300, 19716085, 17210841, 10508990, 30847666). ClinVar contains an entry for this variant (Variation ID: 67835). Based on the evidence outlined above, the variant was classified as uncertain significance.
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	flagged submission	research
Donald Williams Parsons Laboratory, Baylor College of Medicine	RCV000496069	SCV000599943	pathogenic	Long QT syndrome 3	2013-09-13	flagged submission	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	flagged submission	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000496069	SCV000883131	likely pathogenic	Long QT syndrome 3	2018-11-21	flagged submission	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
PreventionGenetics, part of Exact Sciences	RCV004537261	SCV004754871	uncertain significance	SCN5A-related disorder	2024-04-01	no assertion criteria provided	clinical testing	The SCN5A c.3911C>T variant is predicted to result in the amino acid substitution p.Thr1304Met. This variant was reported in individuals with long QT syndrome and Brugada syndrome (Wattanasirichaigoon et al. 1999. PMID: 10508990; Arnestad et al. 2007. PMID: 17210839; Kapplinger et al. 2009. PMID: 19716085; Kapa et al. 2009. PMID: 19841300; Table SVI, Milman et al. 2021. PubMed ID: 34461752). Functional studies showed conflicting evidences of pathogenicity for this variant. Although one study suggested this variant significantly increased persistent sodium currents and faster recovery from inactivation (Wang et al. 2007. PMID: 17210841), another demonstrated no difference from wild type SCN5A (Beyder et al. 2014. PubMed ID: 24613995). This variant also had conflicting interpretations of pathogenicity in the literature ranging from benign to pathogenic (Table S1, Amendola et al. 2015. PMID: 25637381; Table S1, Paludan-Müller et al. 2019. PubMed ID: 31043699; Table SVI, Milman et al. 2021. PubMed ID: 34461752). This variant is reported in 0.031% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of benign, uncertain significance, likely pathogenic, and pathogenic in ClinVar (www.ncbi.nlm.nih.gov/clinvar/variation/67835/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.