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

gnomAD frequency: 0.00009  dbSNP: rs199473278

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766805	SCV000235495	uncertain significance	not provided	2024-05-14	criteria provided, single submitter	clinical testing	Has been reported in individuals referred for indications unrelated to cardiomyopathy/arrhythmia (PMID: 27153395, 26746457); Reported in association with LQTS and atrial fibrillation in the published literature (PMID: 19716085, 21051419, 22685113, 24144883, 24606995, 26213684); Functional studies suggest that this variant does not significantly affect sodium channel function (PMID: 21051419, 26213684); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24144883, 24606995, 22685113, 31983221, 21051419, 25051102, 22581653, 25649125, 28150151, 26746457, 26213684, 28988457, 31737537, 30847666, 34803699, 23631430, 25904541, 37652022, 19716085, 27153395)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000766805	SCV000291811	uncertain significance	not provided	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1596 of the SCN5A protein (p.Phe1596Ile). This variant is present in population databases (rs199473278, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 9716085, 21051419, 25051102, 26213684, 30847666, 31737537, 31983221). ClinVar contains an entry for this variant (Variation ID: 67924). 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 does not substantially affect SCN5A function (PMID: 21051419, 26213684). 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	likely benign	Cardiovascular phenotype	2023-09-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Laboratory for Molecular Medicine, Mass General Brigham 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; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV004528266	SCV000916018	uncertain significance	SCN5A-related disorder	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 Laboratory Services, Illumina	RCV001150546	SCV001311624	uncertain significance	Sick sinus syndrome 1	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 Diagnostics, LLC DBA Color Health	RCV001842369	SCV001354423	uncertain significance	Cardiac arrhythmia	2022-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with isoleucine at codon 1596 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental functional study has suggested that this variant may cause modest changes in the biophysical properties of the sodium channel but is insufficient to cause disease (PMID: 26213684). This variant has been reported in several individuals affected with long QT syndrome (PMID: 19716085), early-onset lone atrial fibrillation (PMID: 21051419, 22685113, 24144883), or atrioventricular nodal reentrant tachycardia (PMID: 29396561). It has also been observed in unaffected related individuals (PMID: 26213684). This variant has been identified in 30/279712 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000766805	SCV001713285	uncertain significance	not provided	2022-02-03	criteria provided, single submitter	clinical testing	BS3, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000183085	SCV001821445	uncertain significance	not specified	2022-08-22	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.4786T>A (p.Phe1596Ile) results in a non-conservative amino acid change located in the ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 248326 control chromosomes (gnomAD). This frequency is approximately equal to that expected for a pathogenic variant in SCN5A causing Arrhythmia (0.0001 vs 0.0001), allowing no conclusion about variant significance. c.4786T>A has been reported in the literature as a VUS in settings of multigene panel testing in individuals/cohorts affected with a variety of cardiac conditions such as Long QT syndrome, Atrial Fibrillation, arrhythmogenic disorders and DCM (example Kapplinger_2009, Olesen_2011-2014, Lieve_2013, Boehringer_2014, Hoshi_2015, Kaltman_2019, Marschall_2019, Mazzarotto_2020). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia/Long QT syndrome. At least two publications report experimental evidence evaluating an impact on protein function (example, Olesen_2011, Hoshi_2015). These results showed no damaging effect of this variant in current-voltage relationship, steady state inactivation and steady state activation properties relative to the WT control. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149713	SCV003838879	uncertain significance	Cardiomyopathy	2021-10-20	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000766805	SCV001743834	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000766805	SCV001925080	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000766805	SCV001959118	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000766805	SCV001968890	uncertain significance	not provided		no assertion criteria provided	clinical testing