ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5686C>T (p.Arg1896Trp) (rs45465995)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000058797 SCV000235542 uncertain significance not provided 2018-08-04 criteria provided, single submitter clinical testing The R1897W variant in the SCN5A gene has been reported in one individual with LQTS and one individual with atrial fibrillation (Kapplinger et al., 2009; Olesen et al., 2012). This variant has also been identified independently and/or in conjunction with additional cardiogenetic variants in individuals referred for arrhythmia genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. Although Kapplinger et al. (2009) did not observe R1897W in >2600 control alleles, the NHLBI Exome Sequencing Project and the 1000 Genomes Project report R1897W was observed in 3/8416 (0.04%) alleles and in 2/1006 (0.2%) alleles from individuals of European background, indicating it may be a rare benign variant in this population.Nevertheless, the R1897W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and this substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000231226 SCV000291823 uncertain significance Brugada syndrome 2019-10-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1897 of the SCN5A protein (p.Arg1897Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs45465995, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual referred for long QT syndrome (LQTS) testing, in an individual affected with early onset atrial fibrillation (AF) whose mother suffered postoperative AF at an old age and did not carry the variant (PMID: 19716085, 22685113), and in a case of sudden infant death (PMID: 28074886). This variant has also been observed during two screenings in the general population in 12 individuals with normal QTc intervals (PMID: 25904541, 26159999). ClinVar contains an entry for this variant (Variation ID: 68003). Experimental studies have shown that this missense change does not change the peak current density of the channel but alters its steady-state inactivation potential (PMID: 22685113). The clinical significance of these findings is unknown. 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.
Fulgent Genetics,Fulgent Genetics RCV000765733 SCV000897101 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
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825448 SCV000966749 uncertain significance not specified 2018-10-10 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Arg1897Trp va riant in SCN5A has been reported in 1 individual with SIDS (Neubauer 2017), 1 in dividual referred for long QT syndrome testing (Kapplinger 2009), and 1 individu al with atrial fibrillation (Olesen 2012). It was also identified in 5 individua ls with normal QT (Ghouse 2015) as well as 0.02% (5/24032) of African chromosome s and 0.01% (17/126720) of European chromosomes by gnomAD (http://gnomad.broadin stitute.org). In vitro functional studies provide some evidence that this varian t may impact protein function (Olesen 2012); however, these types of assays may not accurately represent biological function. In addition, computational predict ion tools and conservation analysis suggest that this variant may impact the pro tein, though this information is not predictive enough to determine pathogenicit y. In summary, while the clinical significance of the p.Arg1897Trp variant is un certain, its frequency suggests that it is more likely to be benign. ACMG/AMP cr iteria applied: PP3, BS1_Supporting.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852547 SCV000995246 uncertain significance Dilated cardiomyopathy 2017-05-19 criteria provided, single submitter clinical testing
Mendelics RCV000987197 SCV001136446 uncertain significance Brugada syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000058797 SCV001248022 uncertain significance not provided 2020-01-01 criteria provided, single submitter clinical testing
Color RCV001182246 SCV001347634 uncertain significance Arrhythmia 2020-01-01 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058797 SCV000090317 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:19716085;PMID:20981092;PMID:22685113).
CSER _CC_NCGL, University of Washington RCV000148859 SCV000190603 uncertain significance Long QT syndrome 2014-06-01 no assertion criteria provided research

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