ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.1939G>A (p.Ala647Thr) (rs548056312)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189223 SCV000242855 uncertain significance not provided 2014-08-04 criteria provided, single submitter clinical testing p.Ala647Thr (GCT>ACT): c.1939 G>A in exon 12 of the SCN2A gene (NM_021007.2). A variant of unknown significance has been identified in the SCN2A gene. The A647T variant 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. The A647T 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. The variant alters a position in the cytoplasmic loop between the 1st and 2nd homologous domains of the SCN2A protein (Shi et al., 2012). A missense mutation in a nearby residue (D649N) has been reported in association with Dravet syndrome, supporting the functional importance of this region of the protein. The A647T substitution occurs at a position that is conserved in mammals; however, Threonine is observed at this position in more distantly related species. In silico analysis is inconsistent in its predictions as to whether or not the this variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether the A647T variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY,INFANT-EPI panel(s).
Invitae RCV000691130 SCV000818873 uncertain significance Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2018-05-12 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 647 of the SCN2A protein (p.Ala647Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs548056312, ExAC 0.02%). This variant has not been reported in the literature in individuals with SCN2A-related disease. ClinVar contains an entry for this variant (Variation ID: 207068). 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.
Illumina Clinical Services Laboratory,Illumina RCV001134702 SCV001294456 uncertain significance Benign familial neonatal-infantile seizures 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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