ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.1384G>A (p.Glu462Lys)

gnomAD frequency: 0.00012  dbSNP: rs199473572
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003654190 SCV000637081 uncertain significance not provided 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 462 of the SCN5A protein (p.Glu462Lys). This variant is present in population databases (rs199473572, gnomAD 0.007%). This missense change has been observed in individuals with SCN5A-related conditions (PMID: 15840476, 19841300, 24721456, 31737537). ClinVar contains an entry for this variant (Variation ID: 67660). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 Diagnostics, LLC DBA Color Health RCV001842279 SCV001356061 uncertain significance Cardiac arrhythmia 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 462 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Brugada syndrome (PMID: 24721456), in a few individual affected with or suspected of having long QT syndrome (PMID: 15840476, 19841300, 31737537), and in an individual affected with dilated cardiomyopathy (PMID: 37904629). This variant has been identified in 7/248440 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.
MGZ Medical Genetics Center RCV002288556 SCV002580684 uncertain significance Brugada syndrome 1 2022-01-18 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002504969 SCV002796912 uncertain significance Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10 2021-10-09 criteria provided, single submitter clinical testing
Institute of Immunology and Genetics Kaiserslautern RCV003509485 SCV004363640 uncertain significance Long QT syndrome 3 2024-01-29 criteria provided, single submitter clinical testing ACMG Criteria: PM2_P,PP3,PP5; Variant was found in heterozygous state
Ambry Genetics RCV004019032 SCV004943814 uncertain significance Cardiovascular phenotype 2022-09-13 criteria provided, single submitter clinical testing The c.1384G>A (p.E462K) alteration is located in exon 11 (coding exon 10) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 1384, causing the glutamic acid (E) at amino acid position 462 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust RCV000058419 SCV000089939 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:15840476;PMID:19841300;PMID:22378279). 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 RCV000148862 SCV000190606 uncertain significance Long QT syndrome 2014-06-01 no assertion criteria provided research

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