ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.5770G>A (p.Ala1924Thr) (rs137854603)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000420298 SCV000514559 likely pathogenic not provided 2016-07-07 criteria provided, single submitter clinical testing The likely pathogenic A1924T variant in the SCN5A gene has been reported in at least one heterozygous individual in association with Brugada syndrome and was absent from over 2,600 control alleles (Rook et al., 1999; Smits et al., 2002, Meregalli et al., 2009; Kapplinger et al., 2010; Amin et al., 2011). Additionally, the A1924T variant was reported as apparently homozygous in identical twin sisters, one of whom presented with sudden cardiac arrest and recurrent sustained ventricular tachycardia and the other with sinus node dysfunction and atrial fibrillation; however, parental testing was not performed to confirmed biallelic inheritance (Lopez et al., 2011; Chiang et al., 2015). The A1924T variant was not observed with any significant frequency in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Furthermore, A1924T 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, and this substitution occurs at a position that is conserved across species. Finally, functional studies in Xenopus oocytes and HEK293 cells demonstrated that the A1924T variant alters sodium channel function (Rook et al., 1999; Kirkton et al., 2012).Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required.
Invitae RCV000058806 SCV000637191 likely benign Brugada syndrome 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000009978 SCV000916016 likely pathogenic Brugada syndrome 1 2018-12-10 criteria provided, single submitter clinical testing The SCN5A c.5770G>A (p.Ala1924Thr) missense variant has described in four studies and found in a heterozygous state in a total of three individuals affected with Brugada syndrome and in a homozygous state in a pair of identical twins affected with sinus node dysfunction (Rook et al. 1999; Meregalli et al. 2009; Amin et al. 2011; Chiang et al. 2015). The p.Ala1924Thr variant was present in one of 1400 controls (Kapplinger et al. 2010) and is reported at a frequency of 0.001084 in the Ashkenazi Jewish population of the Genome Aggregation Database. Functional studies in Xenopus oocytes demonstrated that the variant significantly affected the inward sodium current causing an increase during the action potential upstroke (Rook et al. 1999). Tan et al. (200) demonstrated that the p.Ala1924Thr increased the rate of fast activation of the sodium channel whilst inhibiting the slow activation induced by the calcium-dependent binding of calmodulin. Based on the evidence, the p.Ala1924Thr variant is classified as likely pathogenic for Brugada syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Color RCV001182009 SCV001347318 uncertain significance Arrhythmia 2020-02-13 criteria provided, single submitter clinical testing
OMIM RCV000009978 SCV000030199 pathogenic Brugada syndrome 1 1999-12-01 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058806 SCV000090326 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:10690282;PMID:12106943;PMID:19251209;PMID:20129283). 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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