ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5182G>A (p.Asp1728Asn) (rs763880032)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000771947 SCV000904900 uncertain significance Arrhythmia 2018-09-10 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the transmembrane domain DIV domain of the SCN5A protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/277130 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000183107 SCV000235517 uncertain significance not provided 2017-04-28 criteria provided, single submitter clinical testing The D1729N variant of uncertain significance has not been published as pathogenic or benign to our knowledge. Thisvariant has not been observed at a significant frequency in large population cohorts (Lek et al., 2016; McVean et al.,2012; Exome Variant Server). In addition, D1729N is a semi-conservative amino acid substitution, which mayimpact secondary protein structure as these residues differ in some properties. This substitution also occurs at aposition that is conserved across species, and in silico analysis predicts this variant is probably damaging to theprotein structure/function. Nevertheless, D1729N is classified as a variant of uncertain significance by another clinicallaboratory in ClinVar (ClinVar SCV000545045.1; Landrum et al., 2016).Therefore, additional evidence is needed to determine whether this variant is pathogenic or benign.
Invitae RCV000462910 SCV000545045 uncertain significance Brugada syndrome 2016-04-03 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1729 of the SCN5A protein (p.Asp1729Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs763880032, ExAC 0.006%) but has not been reported in the literature in individuals with a SCN5A-related disease. ClinVar contains an entry for this variant (Variation ID: 201531). 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 C15"). 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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