Submissions for variant NM_000335.5(SCN5A):c.5491C>G (p.Gln1831Glu)

gnomAD frequency: 0.00041  dbSNP: rs199473320

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000058787	SCV000055298	likely benign	Brugada syndrome	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041628	SCV000065324	uncertain significance	not specified	2015-08-03	criteria provided, single submitter	clinical testing	The p.Gln1832Glu variant in SCN5A has been reported in 2 individuals with Brugad a syndrome, 1 infant with sudden death, and 1 individual with focal epilepsy (Ar bustini 2005, Kapplinger 2010, Partemi 2015, Morganstein 2015). The variant has also been identified by our laboratory in 1 adult and 1 infant with DCM, and 1 i ndividual with VT. In vitro functional studies provide some evidence that the p. Gln1832Glu variant may impact protein function (Morganstein 2015), although thes e types of assays may not accurately represent biological function. The p.Gln183 2Glu variant has also been identified in 0.1% (8/9806) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s199473320). The affected amino acid is not well conserved in evolution, raising the possibility that a change may be tolerated. Other computational prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Gln1832Glu variant is uncertain.
GeneDx	RCV001507623	SCV000235536	likely benign	not provided	2020-02-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31983221, 30193851, 20129283, 28370132, 23861362, 29728395, 24631775, 25119684, 16521247, 23414114, 22840528)
Ambry Genetics	RCV000245837	SCV000318818	likely benign	Cardiovascular phenotype	2021-05-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV001507623	SCV000557156	likely benign	not provided	2024-01-11	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000622807	SCV000740418	uncertain significance	Long QT syndrome	2016-07-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001841611	SCV001350894	uncertain significance	Cardiac arrhythmia	2022-12-16	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with glutamic acid at codon 1832 of the SCN5A protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. An experimental functional study has shown that this variant may impact sodium channel function due to protein trafficking defects (PMID: 28370132). This variant has been reported in three individuals affected with or suspected of having Brugada syndrome (PMID: 20129283, 32893267, 36291626, in an infant affected with sudden death who also carried SCN5A p.Arg1944* variant (PMID: 24631775), and in an individual affected with epilepsy (PMID: 25119684). This variant has also been identified in 28/280826 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001507623	SCV001713281	uncertain significance	not provided	2020-09-10	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058787	SCV000090307	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:16521247;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Clinical Genetics, Academic Medical Center	RCV001507623	SCV002034567	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001507623	SCV002038346	uncertain significance	not provided		no assertion criteria provided	clinical testing