Submissions for variant NM_000335.5(SCN5A):c.3389C>T (p.Thr1130Ile)

gnomAD frequency: 0.00003  dbSNP: rs199473197

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587127	SCV000235441	uncertain significance	not provided	2019-07-25	criteria provided, single submitter	clinical testing	Identified in individuals referred for cardiac genetic testing at GeneDx; however, at least one of these probands harbored a pathogenic variant in another cardiac disease-related gene; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 67795; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29247119, 18378609, 21143119, 25175087, 24631775, 28316956, 25904541)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000587127	SCV000545083	uncertain significance	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1131 of the SCN5A protein (p.Thr1131Ile). This variant is present in population databases (rs199473197, gnomAD 0.02%). This missense change has been observed in individual(s) with atrial fibrillation (PMID: 18378609, 24631775). ClinVar contains an entry for this variant (Variation ID: 67795). 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 tolerated. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587127	SCV000700032	uncertain significance	not provided	2017-07-02	criteria provided, single submitter	clinical testing	Variant summary: The c.3392C>T (p.Thr1131Ile) in SCN5A gene is a missense change that involves a non-conserved nucleotide resulting in a non-conservative amino acid substitution located within the cytoplasmic loop between domains II-III. 4/5 in silico tools predict benign, although at least one functional study have shown deleterious effect on the protein function, suggesting a potential causative reason for atrial fibrillation (AF) (Wang, 2010). However, this study has yet to be published in peer-reviewed journal at this time of this review therefore the evidence cannot be unequivocally considered. The variant is present in the large control population dataset of ExAC at a frequency of 4.455e-05 (4/89792 chrs tested), predominantly in individuals of African descent (0.000417; 3/7194 chrs tested). The variant has also been identified in gnomAD dataset at similar frequencies (0.00003; 8/267102 chrs tested). The observed frequency in African cohort exceeds the maximal expected frequency of a pathogenic allele (0.00016) in this gene. However, since no clinical information on ExAC participants are available, the possibility of them being a silent carrier of deleterious variant cannot be ruled out. In addition, the variant was reported in two patients presented with AF and SIDS. Both cases were reported to be of African descent. Since no segregation analysis was done for these patients, there are not enough evidence to classify this variant with confidence. Lastly, the c.3392C>T is cites as VUS by several reputable databases/clinical laboratories. Taking all line of evidence into consideration, the variant was classified as VUS until more information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV001842336	SCV001356413	uncertain significance	Cardiac arrhythmia	2022-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 1131 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). An in vitro functional study has shown that this variant affects the voltage-dependence of channel activation (Wang et al., 2010). This variant has been reported in an individual affected with atrial fibrillation (AF) who has a family history of AF, with both parents and two children affected (PMID: 18378609), and in another individual with sudden unexplained death (PMID: 24631775). This variant has been identified in 8/270004 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.
Ambry Genetics	RCV002453376	SCV002618318	uncertain significance	Cardiovascular phenotype	2023-06-02	criteria provided, single submitter	clinical testing	The p.T1131I variant (also known as c.3392C>T), located in coding exon 18 of the SCN5A gene, results from a C to T substitution at nucleotide position 3392. The threonine at codon 1131 is replaced by isoleucine, an amino acid with similar properties, and is located in the DII/DIII interdomain linker region of the protein. This variant has been detected in an individual with atrial fibrillation, bradycardia, and congestive heart failure, and has been detected in a sudden infant death case (Darbar D et al. Circulation, 2008 Apr;117:1927-35; Wang D et al. Forensic Sci. Int., 2014 Apr;237:90-9). This variant has also been detected in a control cohort; however, details were limited (Kapplinger JD et al. Circ Cardiovasc Genet. 2015 Aug;8(4):582-95). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002498344	SCV002776791	uncertain significance	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2021-07-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587127	SCV004564494	uncertain significance	not provided	2023-03-28	criteria provided, single submitter	clinical testing	The SCN5A c.3392C>T; p.Thr1131Ile variant (rs199473197) is reported in an individual with atrial fibrillation (Darbar 2008) and in a cohort of sudden unexplained deaths (Lin 2017). This variant is also reported in ClinVar (Variation ID: 67795). It is found on eight alleles in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.345). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Darbar D et al. Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation. Circulation. 2008 Apr 15;117(15):1927-35. PMID: 18378609. Lin Y et al. Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths. Circ Cardiovasc Genet. 2017 Dec;10(6):e001839. PMID: 29247119.
All of Us Research Program, National Institutes of Health	RCV001842336	SCV004815016	uncertain significance	Cardiac arrhythmia	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 1131 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). An in vitro functional study has shown that this variant affects the voltage-dependence of channel activation (Wang et al., 2010). This variant has been reported in an individual affected with atrial fibrillation (AF) who has a family history of AF, with both parents and two children affected (PMID: 18378609), and in another individual with sudden unexplained death (PMID: 24631775). This variant has been identified in 8/270004 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058569	SCV000090089	not provided	Atrial fibrillation		no assertion provided	literature only	This variant has been reported as associated with Atrial fibrillation in the following publications (PMID:18378609). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.