rs45465995
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2
The NM_001099404.2(SCN5A):c.5689C>T(p.Arg1897Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1897Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.5689C>T | p.Arg1897Trp | missense_variant | 28/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.5686C>T | p.Arg1896Trp | missense_variant | 28/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.5689C>T | p.Arg1897Trp | missense_variant | 28/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.5686C>T | p.Arg1896Trp | missense_variant | 28/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152194Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000762 AC: 19AN: 249286Hom.: 0 AF XY: 0.0000813 AC XY: 11AN XY: 135228
GnomAD4 exome AF: 0.000155 AC: 226AN: 1461668Hom.: 0 Cov.: 32 AF XY: 0.000149 AC XY: 108AN XY: 727112
GnomAD4 genome ? AF: 0.000105 AC: 16AN: 152312Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74476
ClinVar
Submissions by phenotype
not provided Uncertain:6Other:1
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 05, 2023 | 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) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 03, 2020 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 14, 2024 | 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. - |
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported in the following publications (PMID:19716085;PMID:20981092;PMID:22685113). - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 12, 2020 | 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. - |
Cardiac arrhythmia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 06, 2022 | 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 10, 2018 | 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. - |
Brugada syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 09, 2022 | - - |
SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 17, 2022 | - - |
Long QT syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | May 19, 2017 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 18, 2019 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at