ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.2542A>T (p.Ile848Phe) (rs199473166)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058509 SCV000090029 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:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV000766791 SCV000235410 uncertain significance not provided 2016-06-06 criteria provided, single submitter clinical testing The I848F variant in the SCN5A gene has been reported in one individual referred for LQTS genetic testing, however, no specific personal or family history information was provided (Kapplinger J et al., 2009). I848F 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. Additionally, 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. In contrast, I848F results in a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Finally, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000472294 SCV000545035 uncertain significance Brugada syndrome 2016-04-30 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with phenylalanine at codon 848 of the SCN5A protein (p.Ile848Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with long QT syndrome (LQTS) and referred for LQTS testing (PMID: 25904541, 19716085). ClinVar contains an entry for this variant (Variation ID: 67740). 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: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change that has been reported in affected individuals and has an uncertain impact on protein function. The available evidence is currently insufficient to prove conclusively that this variant causes disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000183004 SCV000540282 uncertain significance not specified 2016-06-23 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Only 1 report; ClinVar: P by GeneDx and Royal Brompton

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