ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.23C>T (p.Pro8Leu) (rs747139785)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189184 SCV000242816 uncertain significance not provided 2013-09-30 criteria provided, single submitter clinical testing p.Pro8Leu (CCG>CTG): c.23 C>T in exon 2 of the SCN2A gene (NM_021007.2). The Pro8Leu missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a semi-conservative amino acid substitution as Proline and Leucine are both uncharged, non-polar residues; however, the removal of a Proline, which has a unique ring structure, may affect the secondary structure of the protein. The variant alters a position in the protein that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, mutations associated with epilepsy have not been previously reported in this region of the protein. Therefore, based on the currently available information, it is unclear whether Pro8Leu is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV001062691 SCV001227507 uncertain significance Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2019-04-16 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 8 of the SCN2A protein (p.Pro8Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs747139785, ExAC 0.002%). This variant has not been reported in the literature in individuals with SCN2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 207031). 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: "Possibly 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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