Submissions for variant NM_000335.5(SCN5A):c.3335C>T (p.Ala1112Val)

gnomAD frequency: 0.00001  dbSNP: rs199473194

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000058565	SCV000760270	uncertain significance	Brugada syndrome	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1113 of the SCN5A protein (p.Ala1113Val). This variant is present in population databases (rs199473194, gnomAD 0.04%). This missense change has been observed in individual(s) with Brugada syndrome or referred for Brugada syndrome testing (PMID: 20129283, 25904541). ClinVar contains an entry for this variant (Variation ID: 67791). 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. Experimental studies have shown that this missense change does not substantially affect SCN5A function (PMID: 24573164). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	RCV001842333	SCV001349315	uncertain significance	Cardiac arrhythmia	2023-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1113 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An experimental study has shown that this variant does not have a significant impact on channel function (PMID: 24573164). This variant has been reported in an individual with long QT or Brugada syndrome (PMID: 25904541) and in an individual referred for Brugada syndrome testing (PMID: 20129283). This variant has been identified in 6/240468 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	RCV002490656	SCV002784128	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	2021-08-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001842333	SCV004815138	uncertain significance	Cardiac arrhythmia	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1113 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An experimental study has shown that this variant does not have a significant impact on channel function (PMID: 24573164). This variant has been reported in an individual with long QT or Brugada syndrome (PMID: 25904541) and in an individual referred for Brugada syndrome testing (PMID: 20129283). This variant has been identified in 6/240468 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058565	SCV000090085	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.