ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.2987C>A (p.Ala996Asp)

dbSNP: rs1263123803
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001309135 SCV001498623 uncertain significance Brugada syndrome 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 996 of the SCN5A protein (p.Ala996Asp). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. 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. 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.
Ambry Genetics RCV002437056 SCV002750665 uncertain significance Cardiovascular phenotype 2018-09-10 criteria provided, single submitter clinical testing The p.A996D variant (also known as c.2987C>A), located in coding exon 16 of the SCN5A gene, results from a C to A substitution at nucleotide position 2987. The alanine at codon 996 is replaced by aspartic acid, an amino acid with dissimilar properties. 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 RCV004005052 SCV004832391 uncertain significance Cardiac arrhythmia 2024-02-22 criteria provided, single submitter clinical testing This missense variant replaces alanine with aspartic acid at codon 996 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has not been identified 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.
GeneDx RCV004762066 SCV005373417 uncertain significance not provided 2023-05-26 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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