ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182967 SCV000235364 uncertain significance not provided 2021-04-06 criteria provided, single submitter clinical testing Reported in association with lone atrial fibrillation, Brugada syndrome, and LQTS (Darbar et al., 2008; Millat et al., 2009; Yamagata et al., 2017); Reported in a family with LQTS in which the proband harbored three clinically relevant variants, however, the SCN5A variant did not independently segregate with disease in family members (Wu et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Electrophysiological studies were not conclusive with regard to effect on protein function (Wu et al., 2018); Reported in ClinVar as a variant of uncertain significance by several clinical laboratories (ClinVar Variant ID# 30048; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30193851, 29449639, 28341781, 15996170, 18378609, 21596231, 25637381, 24784157, 24055113, 22581653, 19026623)
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 Health, Inc RCV001185986 SCV001352306 uncertain significance Arrhythmia 2021-01-13 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 428 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three related individuals affected with atrial fibrillation (PMID: 18378609), one individual with Brugada syndrome (PMID: 28341781), one individual with long QT syndrome (PMID: 19026623) and one case of sudden cardiac death (PMID: 32917565). This variant has been identified in 14/280354 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic RCV000182967 SCV001714695 uncertain significance not provided 2021-01-08 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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