ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.4783T>A (p.Phe1595Ile) (rs199473278)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000247337 SCV000319554 uncertain significance Cardiovascular phenotype 2017-04-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
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.
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
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.
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.
Invitae RCV000229703 SCV000291811 uncertain significance Brugada syndrome 2018-10-01 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%). This variant has been reported 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). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). However, experimental studies have shown that this missense change does not cause significantly altered SCN5A channel activity (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.
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

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