ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.3148G>A (p.Ala1050Thr)

gnomAD frequency: 0.00001  dbSNP: rs1373296470
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000685195 SCV000812668 uncertain significance Brugada syndrome 2018-06-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1050 of the SCN5A protein (p.Ala1050Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (no rsID, ExAC 0.001). This variant has not been reported in the literature in individuals with SCN5A-related disease. 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.
Color Diagnostics, LLC DBA Color Health RCV001841853 SCV001352641 uncertain significance Cardiac arrhythmia 2023-04-07 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 1050 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). A functional study has reported that this variant affects sodium channel function and results in the reduced protein expression (PMID: 36881552). This variant has been reported in an individual affected with Brugada syndrome and in an individual affected with ventricular tachyarrhythmia (PMID: 36881552). This variant has been identified in 2/248836 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV002499215 SCV002814244 uncertain significance 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 2021-07-07 criteria provided, single submitter clinical testing
GeneDx RCV001700447 SCV004014590 likely pathogenic not provided 2023-07-11 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect through reduced sodium Nav1.5 ion channel expression, peak current and upstroke velocity of action potentials and an increase in arrhythmic events (Li et al., 2023); 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: 36881552)
All of Us Research Program, National Institutes of Health RCV001841853 SCV004825370 uncertain significance Cardiac arrhythmia 2023-06-26 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 1050 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). A functional study has reported that this variant affects sodium channel function and results in the reduced protein expression (PMID: 36881552). This variant has been reported in an individual affected with Brugada syndrome and in an individual affected with ventricular tachyarrhythmia (PMID: 36881552). This variant has been identified in 2/248836 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Clinical Genetics, Academic Medical Center RCV001700447 SCV001923466 uncertain significance not provided no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001700447 SCV001962762 uncertain significance not provided no assertion criteria provided clinical testing

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