Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000189214 | SCV000242846 | uncertain significance | not provided | 2013-10-25 | criteria provided, single submitter | clinical testing | p.Asn520Tyr (AAT>TAT): c.1558 A>T in exon 11 of the SCN2A gene (NM_021007.2). The Asn520Tyr missense change in the SCN2A gene 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. This variant is a conservative substitution of one uncharged, polar amino acid for another. It alters a position between the first and second transmembrane domains that is not highly conserved across species; however, other missense mutations in this region of the protein have been reported (E430Q and A575V). In silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Asn520Tyr is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s). |
| Invitae | RCV001037105 | SCV001200502 | uncertain significance | Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11 | 2024-01-15 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 520 of the SCN2A protein (p.Asn520Tyr). 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 variant has not been reported in the literature in individuals affected with SCN2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 207059). 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. |