ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs201641342
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Total submissions: 7
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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
Invitae 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.

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