ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5452G>A (p.Asp1818Asn) (rs137854619)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171695 SCV000050714 uncertain significance Long QT syndrome 2013-06-24 criteria provided, single submitter research
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058782 SCV000090302 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:16922724;PMID:22685113). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV000183199 SCV000235617 uncertain significance not specified 2016-05-11 criteria provided, single submitter clinical testing The D1819N variant in the SCN5A gene was initially reported in the heterozygous state in an individual with long QT syndrome however, this individual was also heterozygous for a pathogenic variant in the KCNH2 gene (Millat et al., 2006). The D1819N variant was subsequently reported in an individual with a borderline prolonged QT interval and a personal and family history of atrial fibrillation; however, D1819N did not segregate with the disease in the family (Olesen et al., 2012). Functional characterization showed that D1819N exhibited a 6-to-10 fold increase in sustained sodium current over wild type SCN5A protein, but no significant difference in peak current density was observed when compared to wild type (Olesen et al., 2012). Furthermore, D1819N is now reported as likely benign in ClinVar by a different clinical laboratory, due to its frequency (0.2%) in a subset of the population (ClinVar SCV000261420.1; Landrum et al., 2015). The D1819N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is well-conserved across species. The D1819N variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret D1819N as a variant of uncertain significance.
Invitae RCV000203774 SCV000261420 likely benign Brugada syndrome 2017-12-29 criteria provided, single submitter clinical testing
OMIM RCV000010005 SCV000030226 pathogenic Long QT syndrome 2/3, digenic 2006-09-01 no assertion criteria provided literature only

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