ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.1289A>G (p.Glu430Gly)

dbSNP: rs796053183
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189210 SCV000242842 likely pathogenic not provided 2012-09-13 criteria provided, single submitter clinical testing p.Glu430Gly (GAA>GGA):c.1289 A>G in exon 10 of the SCN2A gene (NM_021007.2). The Glu430Gly missense change was previously identified in a large family with benign familial neonatal-infantile seizures (BFNIS) and was not detected in 88 control individuals (Herlenius et al., 2007). However, one individual in that family with a history of an infantile seizure did not inherit the variant, which could represent incomplete segregation of Glu430Gly with the phenotype or indicate that individual's seizure was unrelated to BFNIS. The NHLBI ESP Exome Variant Project has not identified Glu430Gly in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as a negatively charged Glutamic acid residue is replaced by a smaller, uncharged and non-polar Glycine residue. Glu430Gly alters a highly conserved position in the loop between the first and second transmembrane domains, and multiple in silico algorithms predict Glu430Gly is likely damaging to protein structure/function. Therefore, the currently available evidence suggests that Glu430Gly may be associated with epilepsy, but the possibility that is a benign variant cannot be entirely excluded. The variant is found in INFANT-EPI panel(s).
Invitae RCV001379442 SCV001577245 likely pathogenic Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11 2020-08-25 criteria provided, single submitter clinical testing This variant has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 24659627). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207056). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with glycine at codon 430 of the SCN2A protein (p.Glu430Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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. This variant disrupts the p.Glu430 amino acid residue in SCN2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17386050). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.

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