ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5479G>A (p.Ala1827Thr) (rs774593360)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183124 SCV000235535 uncertain significance not specified 2014-05-10 criteria provided, single submitter clinical testing p.Ala1828Thr (GCC>ACC): c.5482 G>A in exon 28 of the SCN5A gene (NM_198056.2) The A1828T variant has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The A1828T variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. In silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function. However, mutations in nearby residues (R1826H, R1826C, Q1832E) have been reported in association with arrhythmias, supporting the functional importance of this region of the protein. The A1828T variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in LQT panel(s).
Invitae RCV000477269 SCV000545038 uncertain significance Brugada syndrome 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1828 of the SCN5A protein (p.Ala1828Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs774593360, ExAC 0.01%) but has not been reported in the literature in individuals with a SCN5A-related disease. ClinVar contains an entry for this variant (Variation ID: 201539). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on 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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