ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.3598A>G (p.Thr1200Ala) (rs765909421)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000193068 SCV000248814 uncertain significance not specified 2015-07-22 criteria provided, single submitter clinical testing
GeneDx RCV000193068 SCV000582085 uncertain significance not specified 2017-05-09 criteria provided, single submitter clinical testing A variant of unknown significance has been identified in the SCN2A gene. The T1200A variant has been previously reported in a patient with benign childhood epilepsy with centrotemporal spikes; however, no other information was provided (Berkovic et al., 2004). The T1200A variant is observed in 1/11566 (0.01%) alleles from individuals of Latino background, (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T1200A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species; however, Alanine is observed at this position in one distantly related species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The variant alters a position in the cytoplasmic loop between the second and third homologous domains; however, missense mutations have not been reported in this region of the protein in association with epilepsy (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585018 SCV000693006 uncertain significance not provided 2018-05-01 criteria provided, single submitter clinical testing
Invitae RCV000640631 SCV000762225 uncertain significance Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2019-07-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1200 of the SCN2A protein (p.Thr1200Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs765909421, ExAC 0.009%). This variant has been reported in the literature in an individual affected with benign familial infantile seizures (PMID: 15048894). ClinVar contains an entry for this variant (Variation ID: 212127). 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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