Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000189183 | SCV000242815 | uncertain significance | not provided | 2018-02-22 | criteria provided, single submitter | clinical testing | p.Cys1940Phe (TGT>TTT): c.5819 G>T in exon 27 of the SCN2A gene (NM_021007.2). The Cys1940Phe missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The amino acid substitution is non-conservative as a polar Cysteine residue is replaced by a non-polar Phenylalanine residue and the loss of a Cysteine may affect the formation of disulfide bonds in the SCN2A protein. However, Cys1940Phe alters a position that is not conserved in the C-terminal region of the protein and several in-silico algorithms predict it may be non-pathogenic. Therefore, based on the currently available information, it is unclear whether Cys1940Phe is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s). |
| Invitae | RCV003765202 | SCV004574383 | uncertain significance | Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11 | 2023-03-03 | 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. 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 not expected to disrupt SCN2A protein function. ClinVar contains an entry for this variant (Variation ID: 207030). This variant has not been reported in the literature in individuals affected with SCN2A-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 1940 of the SCN2A protein (p.Cys1940Phe). |