ClinVar Miner

Submissions for variant NM_004974.4(KCNA2):c.1223T>G (p.Val408Gly)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001058042 SCV001222578 likely pathogenic Epileptic encephalopathy, early infantile, 32 2020-03-28 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 408 of the KCNA2 protein (p.Val408Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with KCNA2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNA2 protein function. This variant disrupts the p.Val408 amino acid residue in KCNA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27062609). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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