Submissions for variant NM_001040142.2(SCN2A):c.5645G>A (p.Arg1882Gln)

dbSNP: rs794727444

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000189181	SCV000228475	likely pathogenic	not provided	2014-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000189181	SCV000242813	pathogenic	not provided	2017-03-15	criteria provided, single submitter	clinical testing	The R1882Q variant in the SCN2A has been reported multiple times previously as a de novo change in individuals with epileptic encephalopathy (Carvill et al., 2013; Howell et al., 2015; Trump et al., 2016). The R1882Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1882Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a conserved position predicted to be within the C-terminal cytoplasmic domain, and missense variants at the same position (R1882G, R1882L) have been reported in the Human Gene Mutation Database in association with SCN2A-related disorders (Stenson et al., 2014).
Neurogenetics Laboratory - MEYER, AOU Meyer	RCV000417008	SCV000494507	pathogenic	Epileptic encephalopathy	2016-11-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000176763	SCV000807296	pathogenic	Developmental and epileptic encephalopathy, 11		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516714	SCV003524742	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2024-10-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1882 of the SCN2A protein (p.Arg1882Gln). 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: 23708187, 29844171). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 196039). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN2A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN2A function (PMID: 29844171). This variant disrupts the p.Arg1882 amino acid residue in SCN2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26645390). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001849328	SCV005061853	pathogenic	Seizure	2024-06-24	criteria provided, single submitter	clinical testing
OMIM	RCV000176763	SCV001371871	pathogenic	Developmental and epileptic encephalopathy, 11	2020-10-19	no assertion criteria provided	literature only
GenomeConnect - Simons Searchlight	RCV001265414	SCV001443540	pathogenic	Complex neurodevelopmental disorder	2018-04-06	no assertion criteria provided	provider interpretation	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-04-06 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight.
Neurology Department, Shenzhen Children's Hospital	RCV001847815	SCV002099507	pathogenic	West syndrome; Early infantile epileptic encephalopathy with suppression bursts	2022-02-16	no assertion criteria provided	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV001849328	SCV002106995	likely pathogenic	Seizure	2021-04-05	no assertion criteria provided	literature only
Channelopathy-Associated Epilepsy Research Center	RCV001265414	SCV002605499	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only