ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.4925G>A (p.Gly1642Glu) (rs199473624)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619189 SCV000737682 uncertain significance Cardiovascular phenotype 2016-08-12 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000058724 SCV000832209 uncertain significance Brugada syndrome 2018-04-23 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 1642 of the SCN5A protein (p.Gly1642Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant was reported in an individual referred for long QT diagnostic testing (PMID: 20129283) ClinVar contains an entry for this variant (Variation ID: 67940). 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 and their clinical significance is uncertain. 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.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000999577 SCV001156278 uncertain significance Sudden unexplained death 2018-03-07 criteria provided, single submitter research SCN5A Gly1642Glu has been previously identified in 1 patient referred for Brugada Syndrome genetic testing (Kapplinger et al., 2010) and 1 sudden unexplained death in a teenager (Ambry, Pers. Comm.). We identified this variant in a patient who also suffered a sudden unexplained death and who has a family history of Brugada Syndrome. The variant was found to segregate with disease in our family (3 meiosis). SCN5A Gly1642Glu is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). In silico tools PolyPhen2, SIFT and MutationTaster all predict that this variant is disease causing. In summary this variant is rare in the general population, has been observed in at least 1 other case of Brugada Syndrome and 1 case of SUD, and multiple in silico tools predict it to be deleterious, therefore we classify SCN5A Gly1642Glu as a variant of 'uncertain significance".
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058724 SCV000090244 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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