Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000189495 | SCV000243138 | uncertain significance | not provided | 2014-12-15 | criteria provided, single submitter | clinical testing | p.Asn590Lys (AAT>AAG): c.1770 T>G in exon 14 of the SPTAN1 gene (NM_001130438.2) The N590K variant 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 N590K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is highly conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, previously reported pathogenic mutations in SPTAN1 include in-frame deletions or duplications located within the last four spectrin repeats of the protein, which are essential for dimerization (Saitsu et al., 2010), and the N590K is a missense substitution that is outside this region. Additionally, missense mutations in nearby residues have not been reported. Therefore, based on the currently available information, it is unclear whether the N590K variant is a pathogenic mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s). |
| Invitae | RCV001852509 | SCV002131571 | uncertain significance | Early infantile epileptic encephalopathy with suppression bursts | 2022-10-17 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs781048881, gnomAD 0.0009%). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SPTAN1 protein function. ClinVar contains an entry for this variant (Variation ID: 207322). This variant has not been reported in the literature in individuals affected with SPTAN1-related conditions. This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 590 of the SPTAN1 protein (p.Asn590Lys). |