Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002316829 | SCV000850586 | uncertain significance | Inborn genetic diseases | 2017-04-07 | criteria provided, single submitter | clinical testing | The p.M1128T variant (also known as c.3383T>C), located in coding exon 16 of the SCN2A gene, results from a T to C substitution at nucleotide position 3383. The methionine at codon 1128 is replaced by threonine, an amino acid with similar properties. This alteration was detected in an individual with refractory, repetitive (100 per day) generalized convulsive seizures which onset at age 6. As seizures persisted, his intellect regressed and he is now severely intellectually delayed as an adult (Kobayashi K et al. Epilepsy Res., 2012 Nov;102:109-12). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV001228257 | SCV001400647 | uncertain significance | Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11 | 2023-12-18 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1128 of the SCN2A protein (p.Met1128Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SCN2A-related conditions (PMID: 22591750, 32090326). ClinVar contains an entry for this variant (Variation ID: 589603). 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 with a negative predictive value of 95%. 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. |