ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.5465C>T (p.Ala1822Val) (rs757542048)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000518967 SCV000618775 uncertain significance not provided 2017-06-29 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN2A gene. The A1822V variant was reported in two members of one family with benign familial infantile seizures; however no additional information was provided (Berkovic et al., 2004). The A1822V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution alters a conserved position predicted to be within the C-terminal cytoplasmic domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the A1822V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000691957 SCV000819758 uncertain significance Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2018-05-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1822 of the SCN2A protein (p.Ala1822Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs757542048, ExAC 0.009%). This variant has been observed in two related individuals affected with benign familial infantile seizures (PMID: 15048894). ClinVar contains an entry for this variant (Variation ID: 450222). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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