ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.2240A>C (p.Glu747Ala)

dbSNP: rs747324991
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000603848 SCV000712491 uncertain significance not specified 2016-09-12 criteria provided, single submitter clinical testing The p.Glu747Ala variant in SCN5A has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/66564 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s747324991). Computational prediction tools and conservation analysis suggest th at the p.Glu747Ala variant may not impact the protein, though this information i s not predictive enough to rule out pathogenicity. In summary, the clinical sign ificance of the p.Glu747Ala variant is uncertain.
Color Diagnostics, LLC DBA Color Health RCV001841493 SCV001352626 uncertain significance Cardiac arrhythmia 2022-05-17 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with alanine at codon 747 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/248346 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.
Invitae RCV003541461 SCV002121969 uncertain significance not provided 2023-06-17 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 505332). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. This variant is present in population databases (rs747324991, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 747 of the SCN5A protein (p.Glu747Ala).
Ambry Genetics RCV003302931 SCV004001607 uncertain significance Cardiovascular phenotype 2023-06-05 criteria provided, single submitter clinical testing The p.E747A variant (also known as c.2240A>C), located in coding exon 13 of the SCN5A gene, results from an A to C substitution at nucleotide position 2240. The glutamic acid at codon 747 is replaced by alanine, an amino acid with dissimilar properties. This variant has been detected in a dilated cardiomyopathy cohort; however, details were not provided (Mazzarotto F et al. Circulation, 2020 Feb;141:387-398). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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