ClinVar Miner

Submissions for variant NM_004588.5(SCN2B):c.82C>T (p.Arg28Trp) (rs17121819)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483016 SCV000568846 uncertain significance not provided 2017-02-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN2B gene. The R28W variant has been previously reported in a one individual diagnosed with paroxsymal atrial fibrillation at 55 years of age, who had a history of hypertension, an ECG showing right precordial saddleback type ST-segment elevation, and a negative family history of atrial fibrillation (Watanabe et al., 2009). Additionally, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R28W 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. Watanabe et al. (2009) co-expressed SCN2B and SCN5A in cultured cells and found that SCN2B harboring R28W caused reduced peak sodium current amplitude and a positive shift in the voltage dependence of activation but it did not affect the voltage dependence of inactivation or the persistence of the sodium current, compared to wild-type SCN2B. However, additional functional evidence is needed to further clarify the role of R28W in human disease. Moreover, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. Finally, although a missense variant at the same residue (R28Q) has been reported in the Human Gene Mutation Database in association with atrial fibrillation (Stenson et al., 2014), the clinical significance of this variant also remains to be definitively determined.
OMIM RCV000054539 SCV000083017 pathogenic Atrial fibrillation, familial, 14 2009-06-01 no assertion criteria provided literature only

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