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

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001783018	SCV000616961	pathogenic	not provided	2023-06-14	criteria provided, single submitter	clinical testing	Reported previously in a patient with myoclonic epilepsy and febrile seizures and in a patient with early-onset catatonic syndrome; however, no segregation information was provided (Vykuntaraju K. Gowda et al., 2021; Leroy A et al., 2018); Reported as a maternally inherited variant in a patient with benign familial neonatal seizures (Wolff et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the transmembrane segment S3 of the first homologous domain; This variant is associated with the following publications: (PMID: 32090326, Wu_2021, 30381472, 34782754, 31440721, Gowda_2021, Nieto-Barcelo_2021, 28379373, 35431799, 35715422)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688798	SCV000816422	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 202 of the SCN2A protein (p.Ala202Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SCN2A-related conditions (PMID: 28379373, 30381472, 34782754; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 449147). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as 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
Baylor Genetics	RCV003147500	SCV003834860	likely pathogenic	Developmental and epileptic encephalopathy, 11	2021-03-05	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003147500	SCV004047055	likely pathogenic	Developmental and epileptic encephalopathy, 11		criteria provided, single submitter	clinical testing	The missense variant p.A202V in SCN2A (NM_021007.3) has been reported previously in an individual affected with benign familial neonatal seizures (Wolff et al, 2017). The p.A202V variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Ala at position 202 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The p.A202V missense variant is predicted to be damaging by both SIFT and PolyPhen2. The alanine residue at codon 202 of SCN2A is conserved in all mammalian species. The nucleotide c.605 in SCN2A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001783018	SCV004183783	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	SCN2A: PM1, PM2, PM5, PS2:Moderate, PS4:Moderate, PP3, PP4
Neurology Department, Shenzhen Children's Hospital	RCV001848910	SCV002099474	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-02-16	no assertion criteria provided	clinical testing