Submissions for variant NM_001040142.2(SCN2A):c.122G>A (p.Arg41His)

gnomAD frequency: 0.00001  dbSNP: rs754993031

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001132314	SCV001291972	likely benign	Seizures, benign familial infantile, 3	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV001776120	SCV002013642	uncertain significance	not provided	2020-10-22	criteria provided, single submitter	clinical testing	This substitution is predicted to be within the N-terminal cytoplasmic domain (Shi et al., 2012); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV001856708	SCV002193974	likely benign	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2023-05-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003985483	SCV004112057	uncertain significance	SCN2A-related disorder	2023-05-17	criteria provided, single submitter	clinical testing	The SCN2A c.122G>A variant is predicted to result in the amino acid substitution p.Arg41His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-166152455-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.