ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.1517T>A (p.Met506Lys)

gnomAD frequency: 0.00001  dbSNP: rs760531609
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000998026 SCV001153880 uncertain significance not provided 2019-04-01 criteria provided, single submitter clinical testing
Invitae RCV001242205 SCV001415276 uncertain significance Brugada syndrome 2019-09-30 criteria provided, single submitter clinical testing This sequence change replaces methionine with lysine at codon 506 of the SCN5A protein (p.Met506Lys). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and lysine. This variant is present in population databases (rs760531609, ExAC 0.002%). This variant has been observed in an individual referred for long QT syndrome testing (PMID: 23631430). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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 RCV001842579 SCV001734440 uncertain significance Cardiac arrhythmia 2023-03-02 criteria provided, single submitter clinical testing This missense variant replaces methionine with lysine at codon 506 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having long QT syndrome (PMID: 23631430). This variant has been identified in 1/248192 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.
GeneDx RCV000998026 SCV001779074 uncertain significance not provided 2019-11-05 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in a patient referred to GeneDx for LQTS genetic testing; however, additional clinical information was not provided (Lieve et al., 2013); This variant is associated with the following publications: (PMID: 23631430)
Fulgent Genetics, Fulgent Genetics RCV002481791 SCV002781373 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 2021-10-18 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV001842579 SCV004818690 uncertain significance Cardiac arrhythmia 2023-05-04 criteria provided, single submitter clinical testing This missense variant replaces methionine with lysine at codon 506 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having long QT syndrome (PMID: 23631430). This variant has been identified in 1/248192 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.

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