ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.1841C>T (p.Pro614Leu) (rs143734912)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766773 SCV000242878 uncertain significance not provided 2017-10-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN2A gene. The P614L variant has notbeen published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge.The P614L variant is observed in 7/245,982 (0.003%) alleles in large population cohorts (Lek et al.,2016). The P614L variant is a semi-conservative amino acid substitution, which may impactsecondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals and is predicted to be in the cytoplasmic loop between the first and second homologous domains. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclearwhether this variant is a pathogenic variant or a rare benign variant.
Genetic Services Laboratory,University of Chicago RCV000189246 SCV000596971 uncertain significance not specified 2017-04-13 criteria provided, single submitter clinical testing
Invitae RCV000640618 SCV000762212 uncertain significance Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 614 of the SCN2A protein (p.Pro614Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs143734912, ExAC 0.009%). This variant has not been reported in the literature in individuals with SCN2A-related disease. ClinVar contains an entry for this variant (Variation ID: 207091). 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 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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