ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.4490T>C (p.Met1497Thr) (rs199473263)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619022 SCV000737387 likely pathogenic Cardiovascular phenotype 2016-02-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058682 SCV000090202 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:16414944). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV000183196 SCV000235614 likely pathogenic not provided 2017-03-07 criteria provided, single submitter clinical testing The M1498T likely pathogenic variant in the SCN5A gene has been reported previously in association with LQTS, however no additional clinical or segregation information was provided (Napolitano C et al., 2005). The M1498T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M1498T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense mutation in this same residue (M1498V) and missense mutations in nearby residues (Y1494N, Y1495S, L1501V, G1502S) have been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014), supporting the functional importance of this residue and this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded.
Invitae RCV000548196 SCV000637156 uncertain significance Brugada syndrome 2017-08-23 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 1498 of the SCN5A protein (p.Met1498Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual referred for long QT syndrome genetic testing (PMID: 16414944).   ClinVar contains an entry for this variant (Variation ID: 67902). This variant identified in the SCN5A gene is located in the interdomain linker DIII/DIV region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. It is unclear how this variant impacts the function of this protein. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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