ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.4783T>A (p.Phe1595Ile) (rs199473278)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766805 SCV000235495 uncertain significance not provided 2018-03-29 criteria provided, single submitter clinical testing The F1596I variant of uncertain significance in the SCN5A gene has been previously reported in association with LQTS and atrial fibrillation (Kapplinger et al., 2009; Olesen et al., 2011; Olesen et al, 2012; Christiansen et al., 2014; Olesen et al., 2014; Hoshi et al., 2015). It has also been observed, both independently and in conjunction with additional cardiogenetic variants, in multiple unrelated individuals referred for cardiomyopathy/arrhythmia genetic testing at GeneDx. However, segregation data from published cases and cases observed at GeneDx are not sufficient to clarify the role of this variant in disease. Additionally, this variant has been observed in an individual referred for exome sequencing for an indication unrelated to cardiomyopathy/arrhythmia (Maxwell et al., 2016), and it has been identified in another individual without an arrhythmia phenotype who underwent pharmacogenetic testing (Van Driest et al., 2016). Furthermore, the F1596I variant has been observed in 25/125,810 (0.02%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016).Although this substitution occurs at a position that is conserved across species, F1596I is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, while in silico analysis predicts this variant is probably damaging to the protein structure/function, functional studies in cultured mammalian cells suggest that SCN5A channels harboring F1596I do not affect peak current density or other activation/inactivation parameters of the sodium channel (Olesen et al., 2011). Additional functional studies in HEK293 cells by Hoshi et al. (2015) showed that this variant had only modest effects on steady-state activation, time constant of recovery from inactivation, and persistent current. However, it remains to be determined how the results of these studies in cultured cells translate to a role of the F1596I variant in human disease. Further functional evidence and larger segregation studies are needed to clarify the pathogenicity of this variant.
Invitae RCV000229703 SCV000291811 uncertain significance Brugada syndrome 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with isoleucine at codon 1596 of the SCN5A protein (p.Phe1596Ile). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and isoleucine. This variant is present in population databases (rs199473278, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in several individuals affected with long QT syndrome (PMID: 19716085) and atrial fibrillation (PMID: 21051419, 22685113, 24144883). It has also been observed in unaffected individuals (PMID: 26213684). ClinVar contains an entry for this variant (Variation ID: 67924). This variant has been reported not to substantially affect SCN5A protein function (PMID: 21051419). 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.
Ambry Genetics RCV000247337 SCV000319554 uncertain significance Cardiovascular phenotype 2017-04-03 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000183085 SCV000540286 uncertain significance not specified 2016-10-20 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 5 papers in HGMD, 2 are functional studies that suggest no impact on protein function. Few probands and no apparent segregations; ClinVar: VUS by GeneDx
Fulgent Genetics,Fulgent Genetics RCV000765734 SCV000897102 uncertain significance Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1, autosomal recessive; Progressive familial heart block, type 1A; Paroxysmal familial ventricular fibrillation 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000779406 SCV000916018 uncertain significance SCN5A-Related Disorders 2017-04-27 criteria provided, single submitter clinical testing The SCN5A c.4786T>A (p.Phe1596Ile) missense variant has been reported in five studies of individuals with various cardiac disorders (Kapplinger et al. 2009; Olesen et al. 2012; Christiansen et al. 2014; Boehringer et al. 2014; Hoshi et al. 2015) and described in a heterozygous state in six out of a total of 2814 individuals screened, giving an allele frequency of 0.00178. One of the six individuals also carried two variants in the KCNH2 gene. The variant was also detected in two unaffected individuals in a heterozygous state, one of whom, an unaffected sibling, carried the same additional two variants in the KCNH2 gene as her affected brother (Hoshi et al. 2015). The p.Phe1596Ile variant was absent from 3992 control alleles and is reported at a frequency of 0.00012 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Phe1596 residue is conserved. The variant is described as having no electrophysiological consequence with patch-clamping experiments demonstrating no changes in activation / inactivation parameters or in peak current density compared to wild type (Olesen et al. 2014). Hoshi et al. (2015) confirmed a peak current density similar to wild type with however, a faster recovery from inactivation and increased persistent current compared to wild type. The functional data suggest the p.Phe1596Ile variant has a mild effect, however, due to the prevalence of the variant in cases compared to controls, the p.Phe1596Ile variant is classified as a variant of unknown significance but suspicious for pathogenicity for SCN5A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000183085 SCV001159838 uncertain significance not specified 2018-08-15 criteria provided, single submitter clinical testing The SCN5A c.4786T>A; p.Phe1596Ile variant (rs199473278), is reported in the literature in multiple individuals affected with long QT syndrome (Christiansen 2014, Hoshi 2015, Kapplinger 2009) or atrial fibrillation (Boehringer 2014, Olesen 2012, Olesen 2011), though these studies did not report if this variant cosegregates with disease. This variant is reported in ClinVar (Variation ID: 67924) and is found in the non-Finnish European population with an overall allele frequency of 0.02% (25/125810 alleles) in the Genome Aggregation Database. The phenylalanine at codon 1596 is highly conserved and occurs in a C-terminal region of SCN5A containing other missense variants identified in individuals with Long QT syndrome (Christiansen 2014, Kapplinger 2009); however, computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Further, while electrophysiology studies indicate the p.Phe1596Ile variant has modestly faster recovery from inactivation and slightly higher persistent current than wildtype protein, these defects are thought to be insufficient to cause disease (Hoshi 2015), and protein activity appears otherwise wildtype (Olesen 2011, Hoshi 2015). Due to limited information, the clinical significance of the p.Phe1596Ile variant is uncertain at this time. References: Boehringer T et al. SCN5A mutations and polymorphisms in patients with ventricular fibrillation during acute myocardial infarction. Mol Med Rep. 2014 Oct;10(4):2039-44. Christiansen M et al. Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2. BMC Med Genet. 2014 Mar 7;15:31. Hoshi M et al. Polygenic Case of Long QT Syndrome Confirmed through Functional Characterization Informs the Interpretation of Genetic Screening Results. HeartRhythm Case Rep. 2015 Jul 1;1(4):201-205. Kapplinger JD et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009 Sep;6(9):1297-303. Olesen MS et al. High prevalence of long QT syndrome-associated SCN5A variants in patients with early-onset lone atrial fibrillation. Circ Cardiovasc Genet. 2012 Aug 1;5(4):450-9. Olesen MS et al. Mutations in sodium channel beta-subunit SCN3B are associated with early-onset lone atrial fibrillation. Cardiovasc Res. 2011 Mar 1;89(4):786-93.
Illumina Clinical Services Laboratory,Illumina RCV001150546 SCV001311624 uncertain significance 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color RCV001187578 SCV001354423 uncertain significance Arrhythmia 2020-03-06 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058707 SCV000090227 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:19716085;PMID:21051419;PMID:22685113). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.