ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.3553G>A (p.Ala1185Thr) (rs199473595)

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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 RCV000058576 SCV000090096 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:19996378). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Fulgent Genetics,Fulgent Genetics RCV000765735 SCV000897103 uncertain significance Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1, autosomal recessive; Progressive familial heart block type 1A; Paroxysmal familial ventricular fibrillation 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000638678 SCV000760217 uncertain significance Brugada syndrome 2018-10-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1186 of the SCN5A protein (p.Ala1186Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs199473595, ExAC 0.03%). This variant has been reported in individuals affected with personal and/or family history of arrhythmias (PMID: 19996378, 26743238) and in an individual affected with Brugada syndrome (PMID: 29202755). It has also been observed in a healthy control individual (PMID: 15996170). ClinVar contains an entry for this variant (Variation ID: 67802). 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 tolerated, 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000156315 SCV000206033 uncertain significance not specified 2015-03-12 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Ala1186Thr va riant in SCN5A has been identified in 1 Japanese individual with AV Block and a family history of LQTS (Horigome 2010) and in 1 Asian adult with HCM, who carrie d a pathogenic variant in a different HCM gene (LMM unpublished data). This vari ant has also been identified in 2/5990 East Asian chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199473595). Ala nine (Ala) at position 1186 is not conserved in mammals or evolutionarily distan t species. One mammal (tenrec) has a threonine (Thr) at this position, raising t he possibility that this change may be tolerated. Additional computational predi ction tools suggest that this variant may not impact the protein, though this in formation is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Ala1186Thr variant is uncertain, collectively this data suggests that it is more likely to be benign.

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