Submissions for variant NM_000335.5(SCN5A):c.1652C>T (p.Ala551Val)

gnomAD frequency: 0.00004  dbSNP: rs201641342

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171573	SCV000055304	uncertain significance	Brugada syndrome	2018-04-05	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV003539805	SCV000760237	uncertain significance	not provided	2023-12-21	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 551 of the SCN5A protein (p.Ala551Val). This variant is present in population databases (rs201641342, gnomAD 0.009%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). ClinVar contains an entry for this variant (Variation ID: 191381). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 19706159). 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.
Mendelics	RCV000987227	SCV001136476	uncertain significance	Brugada syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842513	SCV001341204	uncertain significance	Cardiac arrhythmia	2022-12-19	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 551 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant may affect inactivation kinetics of the sodium channel (PMID: 19706159). This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 11/280390 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	RCV002485090	SCV002790638	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	2021-09-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298204	SCV003997299	uncertain significance	Cardiovascular phenotype	2023-03-29	criteria provided, single submitter	clinical testing	The p.A551V variant (also known as c.1652C>T), located in coding exon 11 of the SCN5A gene, results from a C to T substitution at nucleotide position 1652. The alanine at codon 551 is replaced by valine, an amino acid with similar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort, as well as in a control population of a study cohort (Kapplinger JD et al. Circ Cardiovasc Genet, 2015 Aug;8:582-95; Mazzarotto F et al. Circulation, 2020 Feb;141:387-398). Additionally, in vitro analysis showed this alteration may impact protein function (Chiang KC et al. J Biomed Sci, 2009 Aug;16:76). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001842513	SCV004814447	uncertain significance	Cardiac arrhythmia	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 551 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant may affect inactivation kinetics of the sodium channel (PMID: 19706159). This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 11/280390 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.