ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.605C>T (p.Ala202Val)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523939 SCV000616961 uncertain significance not specified 2016-03-29 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN2A gene. The A202V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. This substitution alters a position conserved across species that is predicted to be within the transmembrane segment S3 in the first homologous domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the A202V 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 RCV000688798 SCV000816422 likely pathogenic Seizures, benign familial infantile, 3; Early infantile epileptic encephalopathy 11 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 202 of the SCN2A protein (p.Ala202Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with benign familial neonatal seizures (PMID: 28379373). In addition, this variant has been observed to be de novo in an individual affected with neonatal epilepsy (Invitae). 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: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000720902 SCV000851786 uncertain significance History of neurodevelopmental disorder 2016-02-15 criteria provided, single submitter clinical testing The c.605C>T variant (also known as p.A202V), located in coding exon 4 of the SCN2A gene, results from a C to T substitution at nucleotide position 605. The amino acid change results in alanine to valine at codon 202, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. 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 6498 samples (12996 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. This amino acid alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. In addition, using theBDGPandESEfindersplice site prediction tools, this nucleotidealteration is not predicted to have any significant effect on this splice donor site; however, direct evidence is unavailable.Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV001004701 SCV001164164 pathogenic Seizures, benign familial infantile, 3 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV001004701 SCV001554488 likely pathogenic Seizures, benign familial infantile, 3 criteria provided, single submitter clinical testing

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