ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.3622G>C (p.Glu1208Gln) (rs754401226)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000658059 SCV000779830 uncertain significance not provided 2018-05-12 criteria provided, single submitter clinical testing The E1208Q variant in the SCN4A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E1208Q variant is observed in 7/277202 (0.0025%) alleles in large population cohorts (Lek et al., 2016). The E1208Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret E1208Q as a variant of uncertain significance.
Invitae RCV000534297 SCV000658563 uncertain significance Hyperkalemic Periodic Paralysis Type 1 2017-02-09 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 1208 of the SCN4A protein (p.Glu1208Gln). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs754401226, ExAC 0.03%) but has not been reported in the literature in individuals with a SCN4A-related disease. 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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