ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.4856C>T (p.Thr1619Met) (rs199473282)

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Total submissions: 3
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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 RCV000058715 SCV000090235 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:9521325;PMID:20129283;PMID:10618304;PMID:15520322;PMID:11013131). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneReviews RCV000144031 SCV000188924 pathogenic Brugada syndrome 1 2014-04-10 no assertion criteria provided literature only
Invitae RCV000058715 SCV000637164 likely pathogenic Brugada syndrome 2018-01-27 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1620 of the SCN5A protein (p.Thr1620Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs199473282, ExAC 0.002%). This variant has been reported to segregate with ventricular fibrillation in one family (PMID: 9521325) and with Brugada syndrome in a second family (PMID: 15520322). It has also been observed in two individuals referred for Brugada syndrome genetic testing (PMID: 20129283) and one individual with dilated cardiomyopathy (PMID: 23785128). ClinVar contains entries for this variant (Variation ID: 9371, 67932). This variant identified in the SCN5A gene is located in the transmembrane spanning DIV-S3/S4 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 causes altered channel inactivation rates (PMID: 9521325, 10532948, 10618304, 11029409, 11123251, 11827685). In summary, this variant is a rare missense change that has been shown to segregate with arrhythmias and has an effect on protein function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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