Submissions for variant NM_000335.5(SCN5A):c.5452G>A (p.Asp1818Asn)

gnomAD frequency: 0.00006  dbSNP: rs137854619

Total submissions: 10

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
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	RCV001507624	SCV000261420	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000987198	SCV001136447	benign	Brugada syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001841243	SCV001351137	likely benign	Cardiac arrhythmia	2019-04-14	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001507624	SCV001713282	uncertain significance	not provided	2019-12-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345238	SCV002649717	likely benign	Cardiovascular phenotype	2019-12-15	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV001507624	SCV003821346	uncertain significance	not provided	2021-12-21	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
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.