ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.3688G>A (p.Val1230Met) (rs778820577)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000418825 SCV000525394 likely pathogenic not provided 2016-03-02 criteria provided, single submitter clinical testing The V1230M variant in the SCN4A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V1230M variant was not observed in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V1230M variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The V1230M variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000528478 SCV000658565 uncertain significance Hyperkalemic Periodic Paralysis Type 1 2017-09-21 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 1230 of the SCN4A protein (p.Val1230Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs778820577, ExAC 0.02%). This variant has not been reported in the literature in individuals with SCN4A-related disease. ClinVar contains an entry for this variant (Variation ID: 384521). 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: "Probably Damaging"; Align-GVGD: "Class C15"). 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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