ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.1271T>C (p.Val424Ala) (rs796053181)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189207 SCV000242839 pathogenic not provided 2012-11-20 criteria provided, single submitter clinical testing p.Val424Ala (GTG>GCG): c.1271 T>C in exon 10 of the SCN2A gene (NM_021007.2). The Val424Ala missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Val424Ala 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 conservative, as Valine and Alanine are both uncharged, non-polar amino acids. However, it alters a highly conserved position in the S6 segment of the first transmembrane domain of the protein, and multiple in silico algorithms predict it may be damaging to protein structure/function. This variant has been observed de novo without verified parentage. The variant is found in EPILEPSY panel(s).
Invitae RCV001214974 SCV001386687 uncertain significance Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2019-07-20 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 424 of the SCN2A protein (p.Val424Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with epilepsy and/or a neurodevelopmental disorder (PMID: 29655203). ClinVar contains an entry for this variant (Variation ID: 207053). 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 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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