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 2016-05-23 criteria provided, single submitter clinical testing The R121W variant has been reported in several patients with Brugada syndrome (Kapplinger et al., 2010; Selga et al., 2015), however, familial segregation data was not provided. The R121W variant was also reported in a patient with arrhythmias and was inherited from his father who had a milder phenotype (Holst et al., 2010). The R121W variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, the R121W 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. This substitution occurs at a position that is conserved across species. Furthermore, functional studies show that R121W results in a significant reduction of sodium current and reduced amounts of sodium channels (Holst et al., 2010; Clatot et al., 2012). Therefore, this variant is likely pathogenic.
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 Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000058582 SCV000820708 pathogenic Brugada syndrome 2019-05-28 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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