ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.1190T>C (p.Ile397Thr) (rs199473105)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498420 SCV000589536 likely pathogenic not provided 2016-07-25 criteria provided, single submitter clinical testing The I397T variant has been reported in one individual referred for LQTS genetic testing; clinical and segregation data was not provided (Kapplinger et al., 2009). The I397T variant was not observed in approximately 6,200 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 I397T 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. Furthermore, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Lastly, a pathogenic variant at the same residue (I397V) has been reported in association with sudden unexpected death in epilepsy (SUDEP) (Stenson et al., 2014).Therefore, this variant is likely pathogenic
Invitae RCV001063155 SCV001227990 uncertain significance Brugada syndrome 2019-03-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 397 of the SCN5A protein (p.Ile397Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual referred for long QT syndrome genetic testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67644). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058401 SCV000089921 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.

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