ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.847C>G (p.Pro283Ala) (rs765714006)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000640622 SCV000762216 uncertain significance Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2019-05-09 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 283 of the SCN2A protein (p.Pro283Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs765714006, ExAC 0.01%). This variant has not been reported in the literature in individuals with SCN2A-related disease. 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: "Benign"; 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.
GeneDx RCV000658279 SCV000780050 uncertain significance not provided 2018-05-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN2A gene. The P283A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P283A variant is observed in 1/17248 (0.006%) alleles from individuals of East Asian background (Lek et al., 2016). The P283A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution is predicted to be within the pore forming loop between the S5 and S6 transmembrane segments of the first homologous domain. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

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