Submissions for variant NM_001040142.2(SCN2A):c.235G>C (p.Glu79Gln)

dbSNP: rs1402926276

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001338420	SCV001532085	uncertain significance	Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11	2020-07-15	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SCN2A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with glutamine at codon 79 of the SCN2A protein (p.Glu79Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003321827	SCV004026328	uncertain significance	not provided	2023-05-10	criteria provided, single submitter	clinical testing	PP3, PM2_SUP, PP2
Neuberg Centre For Genomic Medicine, NCGM	RCV005208163	SCV005849380	uncertain significance	Developmental and epileptic encephalopathy, 11		criteria provided, single submitter	clinical testing	The observed missense variant c.235G>C(p.Glu79Gln) in SCN2A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant has 0.0004% allele frequency in gnomAD Exomes. It has been submitted to ClinVar as Uncertain Significance. However, no details are available for independent assessment. The amino acid Glu at position 79 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen-probably damaging, SIFT-damaging and MutationTaster-disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid p.Glu79Gln in SCN2A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.