Submissions for variant NM_001040142.2(SCN2A):c.781G>A (p.Val261Met)

dbSNP: rs1057520413

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000436956	SCV000515383	pathogenic	not provided	2020-07-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate altered channel function (Liao et al., 2010); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24579881, 30776697, 20371507, 22029951, 28379373, 27779742, 28488083, 29100083, 30619928, 31904120, 32090326)
Invitae	RCV001042388	SCV001206066	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2023-05-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN2A function (PMID: 20371507). 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. ClinVar contains an entry for this variant (Variation ID: 378927). This missense change has been observed in individual(s) with benign familial neonatal-infantile seizures or epileptic encephalopathy (PMID: 20371507, 27779742, 28379373, 29100083, 30619928). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 261 of the SCN2A protein (p.Val261Met).
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV002267611	SCV002549764	pathogenic	Seizures, benign familial infantile, 3	2022-06-02	criteria provided, single submitter	clinical testing	This individual is heterozygous for a pathogenic variant, c.781G>A in the SCN2A gene, which results in the amino acid substitution of valine to methionine at residue 261, p.(Val261Met). This variant has not been reported in any population databases (i.e. gnomAD v2.1.1, ESP or dbSNP). However, this variant has been identified, de novo, in multiple individuals with either early infantile epileptic encephalopathy or benign nenonatal or infantile seizures (Zeng et al. 2022 PMID: 35431799; Kong et al. 2019 PMID: 30619928; Wolf et al. 2017 PMID: 28379373 & Liao et al. 2010 PMID: 20371507). Functional studies have shown this variant to have a gain of function effect and is likely to result in a functionally abnormal protein (Hedrich et al, 2019 PMID: 31904120). This variant is considered to be pathogenic according to the ACMG guidelines (evidence used: PS3, PS4_Moderate, PM2, PM6_Strong).
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000436956	SCV001931489	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000436956	SCV001951500	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000436956	SCV001978517	pathogenic	not provided		no assertion criteria provided	clinical testing
Neurology Department, Shenzhen Children's Hospital	RCV001848748	SCV002099490	pathogenic	Benign Neonatal Epilepsy	2022-02-16	no assertion criteria provided	clinical testing
Neurology Department, Shenzhen Children's Hospital	RCV001848747	SCV002099510	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-02-16	no assertion criteria provided	clinical testing
Center of Excellence for Medical Genomics, Chulalongkorn University	RCV002281573	SCV002570050	pathogenic	Episodic ataxia, type 9	2002-09-08	no assertion criteria provided	research
Department of Neurology, Children’s Hospital of Chongqing Medical University	RCV003155938	SCV002577333	likely pathogenic	unclassified developmental and epileptic encephalopathy		no assertion criteria provided	research
Channelopathy-Associated Epilepsy Research Center	RCV002319492	SCV002605491	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV003441147	SCV004167620	pathogenic	Developmental and epileptic encephalopathy, 11	2022-12-05	no assertion criteria provided	clinical testing