ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.4400T>C (p.Val1467Ala) (rs794728883)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183074 SCV000235483 uncertain significance not provided 2017-02-09 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN5A gene. The V1468A variant has not been published as pathogenic or been reported as benign to our knowledge. It was not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V1468A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, a different variant affecting the same residue (V1468F) has been reported in the Human Gene Mutation Database in association with Brugada syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000457728 SCV000545047 uncertain significance Brugada syndrome 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 1468 of the SCN5A protein (p.Val1468Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. 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. ClinVar contains an entry for this variant (Variation ID: 201514). This variant identified in the SCN5A gene is located in the transmembrane DIII-S6 region of the resulting protein (PMID: 25348405), but 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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