ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.3880G>A (p.Glu1294Lys) (rs199473218)

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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 RCV000617507 SCV000736370 uncertain significance Cardiovascular phenotype 2016-11-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058611 SCV000090131 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:11304498). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV000183048 SCV000235457 pathogenic not provided 2013-07-29 criteria provided, single submitter clinical testing The Glu1295Lys mutation in the SCN5A gene has been reported in one individual diagnosed with Long QT syndrome type 3 and was not detected in 600 control chromosomes in this study (Abriel H et al., 2001). Furthermore, Glu1295Lys was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Glu1295Lys results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a positively charged Lysine at a position that is highly conserved across species. Consequently, in silico analysis predicts Glu1295Lys is damaging to the protein structure/function. Mutations in nearby residues (Ala1288Gly, Phe1293Ser) have been reported in association with Brugada syndrome, and Thr1304Met has been reported in association with Long QT syndrome, further supporting the functional importance of this region of the protein. Additionally, functional studies showed that Glu1295Lys caused marked changes in sodium channel activity (Abriel H et al., 2001). In summary, Glu1295Lys in the SCN5A gene is interpreted as a likely disease-causing mutation.The variant is found in DCM panel(s).
Invitae RCV000798001 SCV000937593 uncertain significance Brugada syndrome 2018-09-04 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1295 of the SCN5A protein (p.Glu1295Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with long QT syndrome (PMID: 11304498). ClinVar contains an entry for this variant (Variation ID: 67834). Experimental studies have shown that this missense change disrupts sodium channel activity (PMID: 11304498, 12084774). 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.

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