Submissions for variant NM_001040142.2(SCN2A):c.3956G>A (p.Arg1319Gln)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189142	SCV000242774	pathogenic	not provided	2020-07-02	criteria provided, single submitter	clinical testing	Reported in multiple unrelated families with benign familial neonatal-infantile seizures (BFNIS) and benign familial infantile seizures (BFIS) (Berkovic et al., 2004; Zara et al., 2013); Published functional studies demonstrates loss of Nav1.2 channel function and neuronal hyperexcitability (Scalmani et al., 2006; Misra et al., 2008); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 29307654, 28379373, 28488083, 29635106, 17021166, 23360469, 18479388, 15048894, 28717674, 29655203, 31558572, 32090326)
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000013740	SCV001164131	pathogenic	Seizures, benign familial infantile, 3	2017-05-24	criteria provided, single submitter	clinical testing
Invitae	RCV001218692	SCV001390587	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2023-11-24	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 1319 of the SCN2A protein (p.Arg1319Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with infantile-onset epileptic encephalopathy (PMID: 15048894, 28379373). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12880). 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%. Experimental studies have shown that this missense change affects SCN2A function (PMID: 18479388). This variant disrupts the p.Arg1319 amino acid residue in SCN2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27781031). 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000013740	SCV002026374	pathogenic	Seizures, benign familial infantile, 3	2021-11-05	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS3, PM5_STR, PP1_STR, PS4_MOD, PM1, PM2_SUP, PP3
MGZ Medical Genetics Center	RCV000013740	SCV002581071	pathogenic	Seizures, benign familial infantile, 3	2022-07-07	criteria provided, single submitter	clinical testing
OMIM	RCV000013740	SCV000033987	pathogenic	Seizures, benign familial infantile, 3	2004-04-01	no assertion criteria provided	literature only
OMIM	RCV001260972	SCV001438341	pathogenic	Developmental and epileptic encephalopathy, 11	2004-04-01	no assertion criteria provided	literature only
GenomeConnect - Simons Searchlight	RCV001265327	SCV001443444	pathogenic	Complex neurodevelopmental disorder	2016-08-02	no assertion criteria provided	provider interpretation	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-08-02 and interpreted as Pathogenic. Variant was initially reported on 2015-08-14 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar.
Neurology Department, Shenzhen Children's Hospital	RCV001847599	SCV002099497	pathogenic	Benign familial infantile epilepsy	2022-02-16	no assertion criteria provided	clinical testing
Neurology Department, Shenzhen Children's Hospital	RCV001847598	SCV002099499	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-02-16	no assertion criteria provided	clinical testing
Department of Neurology, Children’s Hospital of Chongqing Medical University	RCV000013740	SCV002577332	likely pathogenic	Seizures, benign familial infantile, 3		no assertion criteria provided	research
Department of Neurology, Children’s Hospital of Chongqing Medical University	RCV003155910	SCV002577337	likely pathogenic	benign sporadic infantile epilepsy		no assertion criteria provided	research
Channelopathy-Associated Epilepsy Research Center	RCV001265327	SCV002605505	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only