ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.361C>T (p.Arg121Trp) (rs199473556)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413145 SCV000490788 likely pathogenic not provided 2020-06-16 criteria provided, single submitter clinical testing Identified in at least two unrelated individuals with Brugada syndrome in published literature (Kapplinger et al., 2010; Selga et al., 2015); Identified in a patient with arrhythmia and was also identified in his father who had a milder phenotype (Holst et al., 2010); Identified in a patient with sudden arrhythmic death syndrome (SADS) who had no cardiac symptoms prior to death and was also identified in his mother and brother who showed Brugada pattern on electrocardiogram (Lahrouchi et al., 2017); Not observed in large population cohorts (Lek et al., 2016); Reported as pathogenic/likely pathogenic in ClinVar but additional evidence is not available (ClinVar Variant ID#67807; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a significant reduction of sodium current and reduced amounts of sodium channels (Holst et al., 2010; Clatot et al., 2012); A different missense change at this residue (R121Q) has been reported as pathogenic in ClinVar (ClinVar SCV#67808; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31737537, 26173111, 28449774, 20395683, 22739120, 23874304, 20129283, 25863800, 23123192, 19606473, 24136861, 25904541, 30662450)
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000522231 SCV000616616 pathogenic Brugada syndrome 1 2017-05-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV000622117 SCV000738156 likely pathogenic Cardiovascular phenotype 2017-09-01 criteria provided, single submitter clinical testing The p.R121W variant (also known as c.361C>T), located in coding exon 2 of the SCN5A gene, results from a C to T substitution at nucleotide position 361. The arginine at codon 121 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in association with Brugada syndrome (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Hertz CL et al. Int. J. Legal Med., 2015 Jul;129:793-800; Leong KM et al. HeartRhythm Case Rep, 2017 Mar;3:167-171). This alteration was also reported in a proband and his father who both had cardiac conduction disease (Holst AG et al. Cardiology, 2010 Apr;115:311-6). In addition, functional studies demonstrate a reduction of sodium current and are consistent with a dominant negative effect through retention in the endoplasmic reticulum (Holst AG et al. Cardiology, 2010 Apr;115:311-6; Clatot J et al. Cardiovasc. Res., 2012 Oct;96:53-63). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000058582 SCV000820708 pathogenic Brugada syndrome 2019-05-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 121 of the SCN5A protein (p.Arg121Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Brugada syndrome (PMID: 19606473, 20129283, 24136861, 26173111, 20395683), syncopes and first degree atrioventricular block (PMID: 20395683), and sudden arrhythmic death syndrome (PMID: 28449774). ClinVar contains an entry for this variant (Variation ID: 67807). This variant has been reported to affect SCN5A protein function (PMID: 20395683, 22739120). This variant disrupts the p.Arg121 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20129283, 24529773). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058582 SCV000090102 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:19606473;PMID:20129283;PMID:20395683;PMID:22739120). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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