ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.889G>A (p.Asp297Asn) (rs794728853)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182952 SCV000235349 uncertain significance not provided 2013-06-03 criteria provided, single submitter clinical testing p.Asp297Asn (GAC>AAC): c.889 G>A in exon 7 of the SCN5A gene (NM_198056.2) The Asp297Asn variant in the SCN5A gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Asp297Asn results in a non-conservative amino acid substitution of a negatively charged Aspartic acid with a neutral Asparagine, this substitution occurs at a position that is not well conserved across species. Consequently, in silico analysis predicts Asp297Asn is benign to the protein structure/function. However, mutations in nearby residues (Gly292Ser, Val294Met, Val300Ile) have been reported in association with Brugada syndrome, supporting the functional significance of this region of the protein. Additionally, the Asp297Asn variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.With the clinical and molecular information available at this time, we cannot definitively determine if Asp297Asn is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).
Invitae RCV000529404 SCV000637209 uncertain significance Brugada syndrome 2018-10-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 297 of the SCN5A protein (p.Asp297Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SCN5A-related disease. This variant identified in the SCN5A gene is located in the transmembrane spanning DI-S5/S6 region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. It is unclear how this variant impacts the function of this protein. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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