ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5491C>G (p.Gln1831Glu) (rs199473320)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000245837 SCV000318818 uncertain significance Cardiovascular phenotype 2016-11-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000058787 SCV000055298 likely benign Brugada syndrome 2013-06-24 criteria provided, single submitter research
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.
GeneDx RCV000041628 SCV000235536 uncertain significance not specified 2016-01-26 criteria provided, single submitter clinical testing The Q1832E variant in the SCN5A gene has been published in at least one individual with Brugada syndrome, while it was absent from more than 2,600 reference alleles (Kapplinger J et al., 2010; Crotti L et al., 2012). This variant has also been reported in association with sudden infant death syndrome in a 5-week-old female who also harbored a R1944X variant in the SCN5A gene (Wang et al., 2014; Morganstein et al., 2015). The NHLBI Exome Sequencing Project reports Q1832E at a low frequency in approximately 3/4,272 African American alleles, indicating it is not a common benign variant in this population. The Q1832E 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 conserved in mammals. Furthermore, missense variants in nearby residues (L1825P, R1826H, I1836T, D1839G) have been reported in the Human Gene Mutation Database in association with arrhythmia or cardiomyopathy (Stenson P et al., 2014), supporting the functional importance of this region of the protein.However, additional evidence is needed to determine whether this variant is pathogenic or benign.
Invitae RCV000058787 SCV000557156 likely benign Brugada syndrome 2017-07-27 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare 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,; 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.
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

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