Submissions for variant NM_001040142.2(SCN2A):c.4904G>A (p.Arg1635Gln)

dbSNP: rs1057520844

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000433186	SCV000518391	pathogenic	not provided	2023-04-07	criteria provided, single submitter	clinical testing	Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30564305, 29655203)
Invitae	RCV002524873	SCV003472554	pathogenic	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2022-10-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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: 380389). This missense change has been observed in individual(s) with clinical features of SCN2A-related conditions (PMID: 29655203, 30564305; external communication). 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 arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1635 of the SCN2A protein (p.Arg1635Gln).
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV003126721	SCV003803781	likely pathogenic	Developmental disorder	2020-03-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003985332	SCV004121371	likely pathogenic	SCN2A-related disorder	2022-11-23	criteria provided, single submitter	clinical testing	The SCN2A c.4904G>A variant is predicted to result in the amino acid substitution p.Arg1635Gln. This variant was reported as de novo variant in one individual with autism spectrum disorder (see additional file 7: Data 4. Guo et al 2018. PubMed ID: 30564305) and also found in another patient with epilepsy and neurodevelopmental disorder (Table S4, Lindy et al 2018. PubMed ID: 29655203). In ClinVar, this variant is interpreted as likely pathogenic/pathogenic (https://preview.ncbi.nlm.nih.gov/clinvar/variation/380389/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.
GenomeConnect - Simons Searchlight	RCV001265330	SCV001443447	likely 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 Likely Pathogenic. Variant was initially reported on 2016-03-25 by GTR ID of laboratory name Ospedale Papa Giovanni XXIIIL Laboratorio di Genetica Medica . The reporting laboratory might also submit to ClinVar.