Submissions for variant NM_001040142.2(SCN2A):c.5752C>T (p.Arg1918Cys)

gnomAD frequency: 0.00011  dbSNP: rs139899756

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000509344	SCV000334115	uncertain significance	not provided	2015-08-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000509344	SCV000617025	uncertain significance	not provided	2016-11-17	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SCN2A gene. The R1918C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1918C variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in an external variant database. The R1918C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution alters a conserved residue predicted to be within the C-terminal cytoplasmic domain, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with SCN2A-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Ambry Genetics	RCV002317801	SCV000849644	likely benign	Inborn genetic diseases	2019-05-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV000509344	SCV001152497	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	SCN2A: BS1
Invitae	RCV001034485	SCV001197842	likely benign	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2024-01-12	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224250	SCV003920428	uncertain significance	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11; Episodic ataxia, type 9	2021-03-30	criteria provided, single submitter	clinical testing	SCN2A NM_021007.2 exon 27 p.Arg1918Cys (c.5752C>T): This variant has not been reported in the literature but is present in 20/125986 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs139899756). This variant is present in ClinVar (Variation ID:282579). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
PreventionGenetics, part of Exact Sciences	RCV003985312	SCV004727357	likely benign	SCN2A-related disorder	2020-09-11	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
GenomeConnect, ClinGen	RCV000509344	SCV000607254	not provided	not provided		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
GenomeConnect - Simons Searchlight	RCV001265283	SCV001443400	uncertain significance	Complex neurodevelopmental disorder	2018-02-16	no assertion criteria provided	provider interpretation	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-02-16 and interpreted as Variant of Uncertain significance. Variant was initially reported on 2016-11-23 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar.