ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1231G>A (p.Val411Met) (rs72549410)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621361 SCV000737789 pathogenic Cardiovascular phenotype 2016-11-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Blueprint Genetics RCV000157478 SCV000207223 pathogenic Long QT syndrome 2014-07-23 no assertion criteria provided clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058408 SCV000089928 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:10961955;PMID:15840476;PMID:16712702;PMID:19716085;PMID:21193062). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000234790 SCV000805142 pathogenic Long QT syndrome 3 2018-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000182964 SCV000235361 pathogenic not provided 2018-06-21 criteria provided, single submitter clinical testing The V411M pathogenic variant has been published previously in several unrelated patients with LQTS, and was not observed in >1500 normal control alleles (Priori et al., 2000; Tester et al., 2005; Hofman-Bang et al., 2006; Horne et al., 2011; Medlock et al., 2012; Carrasco et al., 2012; Stattin et al., 2012). This variant was found to be absent from parental testing and therefore suspected to have occurred de novo in two unrelated individuals with LQTS (Carrasco et al., 2012; Stattin et al., 2012). Additionally, V411M was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Functional studies showed that V411M creates a hyperactive sodium channel (Horne et al., 2011). Although the V411M variant is a conservative amino acid, which is not likely to impact secondary protein structure as these residues share similar properties, the Val411 residue is in the S6 transmembrane helix of domain I and is highly conserved across species. Moreover, in silico analysis predicts V411M is damaging to the protein structure/function.In summary, V411M in the SCN5A gene is interpreted as a pathogenic variant.
Institute of Medical Genetics and Genomics,Sir Ganga Ram Hospital RCV000234790 SCV000240230 pathogenic Long QT syndrome 3 2013-01-01 criteria provided, single submitter research
Invitae RCV000197436 SCV000253977 pathogenic Brugada syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 411 of the SCN5A protein (p.Val411Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (rs72549410, ExAC no frequency). This variant has been reported in the literature in multiple unrelated individuals diagnosed with long QT syndrome (PMID: 10961955, 15840476, 16712702, 19716085, 23098067, 24709866, 23158531), including in one child with long QT syndrome where this variant was suspected to have arisen de novo (PMID: 21193062). ClinVar contains an entry for this variant (Variation ID: 67651). This variant identified in the SCN5A gene is located in the transmembrane DI-S6 region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. Experimental studies have shown that this missense change leads to prolonged action potential repolarization (PMID: 21193062). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000157478 SCV000740425 pathogenic Long QT syndrome 2017-06-26 criteria provided, single submitter clinical testing

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