ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.4856C>T (p.Thr1619Met)

gnomAD frequency: 0.00001  dbSNP: rs199473282
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001836727 SCV000637164 pathogenic not provided 2024-01-08 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1620 of the SCN5A protein (p.Thr1620Met). This variant is present in population databases (rs199473282, gnomAD 0.0009%). This missense change has been observed in individual(s) with Brugada syndrome and/or clinical features of SCN5A-related conditions (PMID: 9521325, 15520322, 20129283, 23785128, 29728395, 30847666, 34076677). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67932). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 9521325, 10532948, 10618304, 11029409, 11123251, 11827685). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health RCV001842371 SCV001340219 likely pathogenic Cardiac arrhythmia 2021-09-28 criteria provided, single submitter clinical testing This missense variant replaces threonine with methionine at codon 1620 in the transmembrane domain DIV of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Multiple functional studies have generally shown that this variant alters the sodium channel function (PMID: 9521325, 10532948, 10618304, 11029409, 11123251, 11827685, 30050137). This variant has been reported in multiple unrelated individuals affected with Brugada syndrome (PMID: 15520322, 20129283, 25904541) and has been shown to segregate with disease in six relatives from a family (PMID: 9521325, 10662748, 15520322). This variant has been identified in 1/250918 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
GeneDx RCV001836727 SCV002097418 likely pathogenic not provided 2022-02-08 criteria provided, single submitter clinical testing Multiple studies have examined the functional effect of the T1620M variant, with the general conclusion that this variant impacts sodium ion channel function (Chen et al., 1998; Dumaine et al., 1999; Makita et al., 2000; Shirai et al., 2002); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11786529, 11827685, 10618304, 11013131, 23785128, 29728395, 30662450, 30847666, 15520322, 20129283, 10532948, 11029409, 11123251, 9521325, 34135346, 33131149)
Institute of Human Genetics, Heidelberg University RCV000144031 SCV002757810 likely pathogenic Brugada syndrome 1 2022-06-15 criteria provided, single submitter clinical testing reported as secondary finding
Fulgent Genetics, Fulgent Genetics RCV002477202 SCV002797462 likely pathogenic Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10 2021-07-01 criteria provided, single submitter clinical testing
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 not provided Brugada syndrome 1 no assertion provided literature only

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