ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.1558A>T (p.Asn520Tyr) (rs746957483)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189214 SCV000242846 uncertain significance not provided 2013-10-25 criteria provided, single submitter clinical testing p.Asn520Tyr (AAT>TAT): c.1558 A>T in exon 11 of the SCN2A gene (NM_021007.2). The Asn520Tyr missense change in the SCN2A gene 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. This variant is a conservative substitution of one uncharged, polar amino acid for another. It alters a position between the first and second transmembrane domains that is not highly conserved across species; however, other missense mutations in this region of the protein have been reported (E430Q and A575V). In silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Asn520Tyr is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Invitae RCV001037105 SCV001200502 uncertain significance Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2019-02-11 criteria provided, single submitter clinical testing This sequence change replaces asparagine with tyrosine at codon 520 of the SCN2A protein (p.Asn520Tyr). The asparagine residue is weakly conserved and there is a large physicochemical difference between asparagine and tyrosine. This variant is present in population databases (rs746957483, ExAC 0.003%). This variant has not been reported in the literature in individuals with SCN2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 207059). 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: "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.

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