Submissions for variant NM_001040142.2(SCN2A):c.1987C>G (p.Leu663Val)

dbSNP: rs1017711579

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002317571	SCV000851090	uncertain significance	Inborn genetic diseases	2016-06-21	criteria provided, single submitter	clinical testing	The p.L663V variant (also known as c.1987C>G), located in coding exon 11 of the SCN2A gene, results from a C to G substitution at nucleotide position 1987. The leucine at codon 663 is replaced by valine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV001862076	SCV002175467	uncertain significance	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2020-12-30	criteria provided, single submitter	clinical testing	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. 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"). This variant has not been reported in the literature in individuals with SCN2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 589861). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with valine at codon 663 of the SCN2A protein (p.Leu663Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine.
Revvity Omics, Revvity	RCV003141723	SCV003820774	uncertain significance	not provided	2021-04-27	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV003338766	SCV004047987	uncertain significance	Developmental and epileptic encephalopathy, 11		criteria provided, single submitter	clinical testing	The missense variant c.1987C>G (p.Leu663Val) in SCN2A gene has been submitted to ClinVar as a Variant of Uncertain Significance. It has not been reported in affected individuals. This variant is reported with the allele frequency (0.0004%) in the gnomAD and novel in 1000 genome database. The amino acid Leu at position 663 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Leu663Val in SCN2A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance.