ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.2236G>A (p.Glu746Lys) (rs199473582)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498105 SCV000589535 uncertain significance not specified 2017-06-22 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN5A gene. The E746K variant was originally reported in a patient with ARVC who also exhibited provocable coved-type ST-segment elevation in right precordial leads on ECG (Peters, 2008). Kapplinger et al. (2010) identified E746K in three unrelated probands with suspected Brugada syndrome, although specific clinical details and familial segregation information was not provided. Similarly, Sabater-Molina et al. (2013) reported E746K in a cohort of patients with long QT syndrome (LQTS) and/or Brugada syndrome, but did not provide specific clinical details. The E746K 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). E746K 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. Moreover, this substitution occurs at a position that is conserved in mammals. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000058489 SCV000954490 uncertain significance Brugada syndrome 2019-07-16 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 746 of the SCN5A protein (p.Glu746Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs199473582, ExAC 0.01%). This variant has been observed in individuals referred for Brugada syndrome genetic testing (PMID: 20129283) and has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 18304999). ClinVar contains an entry for this variant (Variation ID: 67721). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Mendelics RCV000987216 SCV001136465 uncertain significance Brugada syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058489 SCV000090009 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). 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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