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

gnomAD frequency: 0.00001  dbSNP: rs1373296470

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	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	2025-04-03	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 (PMID: 36881552); 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: 37830612, 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