ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.3456G>C (p.Gln1152His) (rs776705132)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000774286 SCV000907988 uncertain significance Arrhythmia 2018-10-20 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the linker region between transmembrane domains DII and DIII 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 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 14/266358 chromosomes (13/28872 South Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Invitae RCV000808303 SCV000948407 uncertain significance Brugada syndrome 2018-07-26 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 1153 of the SCN5A protein (p.Gln1153His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs776705132, ExAC 0.04%). This variant has not been reported in the literature in individuals with SCN5A-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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