Submissions for variant NM_001040142.2(SCN2A):c.2995G>A (p.Glu999Lys)

dbSNP: rs796053126

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189130	SCV000242762	pathogenic	not provided	2025-05-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); This substitution is predicted to be in the cytoplasmic loop between the second and third homologous domains; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29655203, 32090326, 26648591, 26993267, 23935176, 27867041, 28078312, 28837158, 30182498, 31054490, 31780880, 32400968, 31440721, 34380004, 35431799, 37578743, 37329172, 38651838)
NeuroMeGen, Hospital Clinico Santiago de Compostela	RCV000496128	SCV000586737	likely pathogenic	Developmental and epileptic encephalopathy, 11		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814425	SCV000954835	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2024-04-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 999 of the SCN2A protein (p.Glu999Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early onset epileptic encephalopathy (PMID: 23935176, 26648591, 26993267, 27867041, 28379373). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 206981). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN2A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000496128	SCV001520569	pathogenic	Developmental and epileptic encephalopathy, 11	2020-02-06	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV005250033	SCV005900651	pathogenic	SCN2A-related disorder	2023-11-21	criteria provided, single submitter	clinical testing	Missense variation is an established mechanism of disease for SCN2A-related disorders (PMID: 26291284). The c.2995G>A (p.Glu999Lys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as a heterozygous change in patients with focal seizures, developmental and epileptic encephalopathy, Ohtahara syndrome, and severe intellectual disability (PMID: 23935176, 26648591, 26993267, 27867041, 28379373), including de novo detection in multiple affected individuals (PMID: 26993267, RCIGM Internal data). A different amino acid change at the same residue (p.Glu999Val) has been previously reported in an individual with developmental and epileptic encephalopathy (PMID: 26993267). Functional studies indicate this variant may alter sodium channel activity (PMID: 32400968). The c.2995G>A (p.Glu999Lys) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, c.2995G>A (p.Glu999Lys) is classified as Pathogenic.
GenomeConnect - Simons Searchlight	RCV001265328	SCV001443445	pathogenic	Complex neurodevelopmental disorder	2016-07-14	no assertion criteria provided	provider interpretation	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-07-14 and interpreted as Pathogenic. Variant was initially reported on 2015-07-31 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar.
Neurology Department, Shenzhen Children's Hospital	RCV001847839	SCV002099460	pathogenic	West syndrome	2022-02-16	no assertion criteria provided	clinical testing
Neurology Department, Shenzhen Children's Hospital	RCV001847840	SCV002099501	pathogenic	Epilepsy of infancy with migrating focal seizures	2022-02-16	no assertion criteria provided	clinical testing
Department of Neurology, Children’s Hospital of Chongqing Medical University	RCV003155928	SCV002577346	pathogenic	Developmental and epileptic encephalopathy, 30		no assertion criteria provided	research
Channelopathy-Associated Epilepsy Research Center	RCV001265328	SCV002605500	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only