Submissions for variant NM_000335.5(SCN5A):c.554C>T (p.Ala185Val)

gnomAD frequency: 0.00001  dbSNP: rs199473067

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001842388	SCV001355165	uncertain significance	Cardiac arrhythmia	2023-10-22	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 185 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). This variant is found within a highly conserved transmembrane domain (a.a. 132-410). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual with suspected Brugada syndrome (PMID: 20129283). Additionally, this variant has been reported in one case of fetal dilated cardiomyopathy; however, the proband's mother who is also a carrier is asymptomatic (Bertucci 2020 DOI: 10.31907/2309-4400.2020.08.06). This variant has been identified in 4/246872 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003541030	SCV001377484	uncertain significance	not provided	2024-11-26	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 185 of the SCN5A protein (p.Ala185Val). This variant is present in population databases (rs199473067, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of Brugada syndrome (PMID: 20129283). ClinVar contains an entry for this variant (Variation ID: 67998). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Fulgent Genetics, Fulgent Genetics	RCV002477204	SCV002797052	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	2021-11-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001842388	SCV004839512	uncertain significance	Cardiac arrhythmia	2024-09-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 185 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). This variant is found within a highly conserved transmembrane domain (a.a. 132-410). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual with suspected Brugada syndrome (PMID: 20129283). Additionally, this variant has been reported in one case of fetal dilated cardiomyopathy; however, the proband's mother who is also a carrier is asymptomatic (Bertucci 2020 DOI: 10.31907/2309-4400.2020.08.06). This variant has been identified in 4/246872 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	RCV000058792	SCV000090312	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.