Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000189191 | SCV000242823 | uncertain significance | not provided | 2023-10-25 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); 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; This substitution is predicted to be within the intracellular loop between the S2 and S3 transmembrane segments of the first homologous domain; Has not been previously published as pathogenic or benign to our knowledge |
| Invitae | RCV001852501 | SCV002150247 | uncertain significance | Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11 | 2023-11-12 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 181 of the SCN2A protein (p.Leu181Phe). This variant is present in population databases (rs796053170, gnomAD 0.0009%). 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: 207038). 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 with a positive 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. |
| Ambry Genetics | RCV002514056 | SCV003559540 | uncertain significance | Inborn genetic diseases | 2023-05-26 | criteria provided, single submitter | clinical testing | The c.543A>C (p.L181F) alteration is located in exon 5 (coding exon 4) of the SCN2A gene. This alteration results from an A to C substitution at nucleotide position 543, causing the leucine (L) at amino acid position 181 to be replaced by a phenylalanine (F). Based on data from gnomAD, the C allele has an overall frequency of <0.001% (1/250920) total alleles studied. The highest observed frequency was 0.001% (1/113494) of European (non-Finnish) alleles. This amino acid position is well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |