ClinVar Miner

Submissions for variant NM_001037.5(SCN1B):c.352G>T (p.Asp118Tyr)

dbSNP: rs761925369
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000171040 SCV000223604 uncertain significance not provided 2014-05-16 criteria provided, single submitter clinical testing p.Asp118Tyr (GAC>TAC): c.352 G>T in exon 3 of the SCN1B gene (NM_001037.4). The D118Y variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The D118Y variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D118Y 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 in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, mutations in nearby residues have not been reported in association with arrhythmias. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. Brugada syndrome is primarily an autosomal dominant disease characterized by ST segment elevation on ECG in the absence of structural heart disease, associated with increased risk for syncope, ventricular tachyarrhythmia and sudden cardiac death. Brugada syndrome is most frequently caused by mutations in the genes encoding cardiac ion channel proteins, which regulate sodium and calcium movement in and out of cardiac cells (Fowler S et al., 2008; Hedley P et al., 2009). Although rare, mutations in the SCN1B gene have been reported in association with Brugada syndrome (BrugadaRet al., 2012). The variant is found in BRUGADA panel(s).
Invitae RCV000797071 SCV000936611 uncertain significance Brugada syndrome 5 2023-12-20 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 118 of the SCN1B protein (p.Asp118Tyr). This variant is present in population databases (rs761925369, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SCN1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 190861). 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. 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.

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