ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.5686C>T (p.Arg1896Trp)

gnomAD frequency: 0.00009  dbSNP: rs45465995
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000058797 SCV000235542 uncertain significance not provided 2023-07-05 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Patch-clamp studies revealed R1897W may impact channel steady-state inactivation; however, other electrophysiological properties were not significantly different from wild-type (Olesen et al., 2012); This variant is associated with the following publications: (PMID: 25637381, 26159999, 24144883, 25410959, 28150151, 22581653, 26332594, 22995991, 27332903, 28074886, 26835069, 30669290, 25904541, 34621001, 29759671, 31983221, 19716085, 22685113, 33071830, 34461752, 29709244, 30193851, 31737537, 35932045)
Invitae RCV000058797 SCV000291823 uncertain significance not provided 2024-01-14 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1897 of the SCN5A protein (p.Arg1897Trp). This variant is present in population databases (rs45465995, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 19716085, 22685113, 28074886, 30193851, 34461752). ClinVar contains an entry for this variant (Variation ID: 68003). 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 affects SCN5A function (PMID: 22685113). 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; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10 2022-02-17 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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 Primary 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
Color Diagnostics, LLC DBA Color Health RCV001842389 SCV001347634 uncertain significance Cardiac arrhythmia 2022-12-06 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 1897 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). A functional study has shown that this variant changes the steady-state inactivation potential of the channel (PMID: 22685113). However, clinical relevance of this observation is not clear. This variant has been reported in an individual referred for long QT syndrome testing (PMID: 19716085), in an individual affected with early onset atrial fibrillation whose mother diagnosed with postoperative atrial fibrillation at an old age but did not carry this variant (PMID: 22685113), and in a case of sudden infant death (PMID: 28074886). This variant has also been observed in 12 control individuals with normal QTc intervals (PMID: 25904541, 26159999). This variant has been identified in 23/280692 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000058797 SCV001477582 uncertain significance not provided 2020-03-12 criteria provided, single submitter clinical testing The SCN5A c.5689C>T; p.Arg1897Trp variant (rs45465995) is reported in the literature in a few individuals, one affected with long QT syndrome (Kapplinger 2009), one with sudden infant death syndrome (Neubauer 2017), one with unexplained cardiac arrest (Tadros 2017), and one with atrial fibrillation (AF) whose mother also had AF but did not carry the variant (Olesen 2012). This variant is also reported in control individuals, including several with normal QT intervals (Ghouse 2015, Kapplinger 2015). This variant is reported in ClinVar (Variation ID: 68003), and is found in the general population with an overall allele frequency of 0.0082% (23/280692 alleles) in the Genome Aggregation Database. The arginine at codon 1897 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show alterations to the steady-state inactivation potential (Ghouse 2015). Due to conflicting information, the clinical significance of the p.Arg1897Trp variant is uncertain at this time. References: Ghouse J et al. Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. Eur Heart J. 2015 Oct 1;36(37):2523-9. 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. Kapplinger JD et al. Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A-Encoded Na(v)1.5 Cardiac Sodium Channel. Circ Cardiovasc Genet. 2015 Aug;8(4):582-95. Neubauer J et al. Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases. Eur J Hum Genet. 2017 Apr;25(4):404-409. 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. Tadros R et al. Yield and Pitfalls of Ajmaline Testing in the Evaluation of Unexplained Cardiac Arrest and Sudden Unexplained Death: Single-Center Experience With 482 Families. JACC Clin Electrophysiol. 2017 Dec 11;3(12):1400-1408.
Mayo Clinic Laboratories, Mayo Clinic RCV000058797 SCV001713279 uncertain significance not provided 2020-12-03 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003486636 SCV004239681 uncertain significance Cardiomyopathy 2022-09-09 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV001842389 SCV004815000 uncertain significance Cardiac arrhythmia 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 1897 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). A functional study has shown that this variant changes the steady-state inactivation potential of the channel (PMID: 22685113). However, clinical relevance of this observation is not clear. This variant has been reported in an individual referred for long QT syndrome testing (PMID: 19716085), in an individual affected with early onset atrial fibrillation whose mother diagnosed with postoperative atrial fibrillation at an old age but did not carry this variant (PMID: 22685113), and in a case of sudden infant death (PMID: 28074886). This variant has also been observed in 12 control individuals with normal QTc intervals (PMID: 25904541, 26159999). This variant has been identified in 23/280692 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 RCV004017380 SCV004849281 uncertain significance Cardiovascular phenotype 2019-01-18 criteria provided, single submitter clinical testing The c.5689C>T (p.R1897W) alteration is located in exon 28 (coding exon 27) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 5689, causing the arginine (R) at amino acid position 1897 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
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
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000058797 SCV001978454 uncertain significance not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000058797 SCV001979679 uncertain significance not provided no assertion criteria provided clinical testing

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