ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.3157G>A (p.Glu1053Lys) (rs137854617)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058552 SCV000090072 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000755695 SCV000883127 likely pathogenic Long QT syndrome 3 2018-11-21 criteria provided, single submitter clinical testing
Invitae RCV000469648 SCV000545106 uncertain significance Brugada syndrome 2018-08-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1053 of the SCN5A protein (p.Glu1053Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs137854617, ExAC 0.03%). This variant has been reported in individuals with Brugada syndrome (PMID: 11901046, 19716085, 15579534, 20129283, 23321620), long QT syndrome (PMID: 20403459, 19026623), and atrial fibrillation (PMID: 18378609). This variant has also been observed in an individual who suffered sudden cardiac death; however, she also carried a SCN5A deletion, while an unaffected family member was homozygous for this p.Glu1053Lys variant (PMID: 28391114). ClinVar contains an entry for this variant (Variation ID: 9400). 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 disruptive, but these predictions have not been confirmed by published functional studies. Experimental studies have shown conflicting results. While this variant was shown to impair ankyrin-G binding and did not localize properly in cardiomyocytes in one experimental study (PMID: 15579534), a second study showed that channel activation in cardiomyocytes was unaffected in cells with reducted ankyrin-G expression and that neither ankyrin-G binding nor improper localization affected the function of the channel (PMID: 18180363). The clinical significance of these findings is unclear. 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.
OMIM RCV000010002 SCV000030223 pathogenic Brugada syndrome 1 2008-04-15 no assertion criteria provided literature only
OMIM RCV000022945 SCV000044236 pathogenic Atrial fibrillation, familial, 10 2008-04-15 no assertion criteria provided literature only

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