ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1282G>A (p.Glu428Lys) (rs199473111)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182967 SCV000235364 uncertain significance not provided 2018-05-24 criteria provided, single submitter clinical testing The E428K variant of uncertain significance in the SCN5A gene has been published previously in patients with atrial fibrillation and Brugada syndrome, and in at least one control individual (Darbar et al., 2008; Maekawa et al., 2005; Yamagata et al., 2017). Maekawa et al. (2005) initially reported E428K in one published Japanese control individual, but it was not present in their cohort of individuals with arrhythmias. Subsequently, Darbar et al. (2008) reported E428K in three individuals from one family with atrial fibrillation. Yamagata et al. (2017) reported E428K in a cohort of Japanese individuals with Brugada syndrome. Additionally, the E428K variant is observed in 2/18,868 alleles (0.01%) from individuals of East Asian ancestry in large population cohorts (Lek et al., 2016). The E428K 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nonetheless, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Fulgent Genetics,Fulgent Genetics RCV000765740 SCV000897108 uncertain significance Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1, autosomal recessive; Progressive familial heart block, type 1A; Paroxysmal familial ventricular fibrillation 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000817255 SCV000957805 uncertain significance Brugada syndrome 2019-05-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 428 of the SCN5A protein (p.Glu428Lys). 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 (rs199473111, ExAC 0.02%). This variant has been observed in several individuals affected with atrial fibrillation, Brugada syndrome or long QT syndrome (PMID: 18378609, 24784157, 28341781, 29449639, 19026623, 15996170). However, in one family another variant was also identified in KCNH2, which suggests that this c.1282G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 30048). This variant has been reported to have conflicting or insufficient data to determine the effect on SCN5A protein function (PMID: 29449639). 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.
Color RCV001185986 SCV001352306 uncertain significance Arrhythmia 2020-04-15 criteria provided, single submitter clinical testing
OMIM RCV000022950 SCV000044241 pathogenic Atrial fibrillation, familial, 10 2008-04-15 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000148855 SCV000089931 not provided Atrial fibrillation no assertion provided literature only This variant has been reported as associated with Atrial fibrillation in the following publications (PMID:18378609). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington RCV000148855 SCV000190599 uncertain significance Atrial fibrillation 2014-06-01 no assertion criteria provided research

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