ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.1376A>C (p.Glu459Ala) (rs184769423)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000189212 SCV000152614 likely benign not specified 2016-05-12 criteria provided, single submitter clinical testing
GeneDx RCV000189212 SCV000242844 uncertain significance not specified 2017-07-21 criteria provided, single submitter clinical testing The E459A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E459A variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project and the 1000 Genomes Project. This substitution occurs at a position predicted to be within the intracellular loop between the first and second homologous domain where amino acids with similar properties to Glutamic acid are tolerated across species. However, the E459A 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678841 SCV000805030 uncertain significance Pyridoxine-dependent epilepsy 2017-04-21 criteria provided, single submitter clinical testing
Invitae RCV000687428 SCV000814993 uncertain significance Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2018-04-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 459 of the SCN2A protein (p.Glu459Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs184769423, ExAC 0.04%). This variant has not been reported in the literature in individuals with SCN2A-related disease. ClinVar contains an entry for this variant (Variation ID: 130213). 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.
Ambry Genetics RCV000719876 SCV000850747 likely benign History of neurodevelopmental disorder 2017-01-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,In silico models in agreement (benign)
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000733650 SCV000861740 uncertain significance not provided 2018-06-14 criteria provided, single submitter clinical testing

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