ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.4223T>C (p.Val1408Ala) (rs1574716488)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000805576 SCV000945536 likely pathogenic Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2019-01-15 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 1408 of the SCN2A protein (p.Val1408Ala). 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). This variant has been observed to be de novo in an individual affected with neonatal seizures (Invitae). 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: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853351 SCV000996216 likely pathogenic Early infantile epileptic encephalopathy 11 2018-11-25 criteria provided, single submitter clinical testing This variant has not been previously reported or functionally characterized in the literature to our knowledge. It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The variant is located in the functional domain of the protein (ion transport domain). The c.4223T>C (p.Val1408Ala) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the current available evidence, the c.4223T>C (p.Val1408Ala) variant is classified as likely pathogenic.

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