Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000186895 | SCV000240466 | uncertain significance | not provided | 2014-10-24 | criteria provided, single submitter | clinical testing | p.Arg134Ser (AGG>AGC): c.402 G>C in exon 5 of the CHRNA2 gene (NM_000742.3). A variant of unknown significance has been identified in the CHRNA2 gene. The R134S 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 R134S 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 conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this amino acid substitution does not occur within the transmembrane region of the protein, where the vast majority of pathogenic missense mutations have been identified in association with epilepsy (Steinlein et al., 2010). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). |
| Labcorp Genetics |
RCV003583152 | SCV004250872 | uncertain significance | Autosomal dominant nocturnal frontal lobe epilepsy | 2024-05-27 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 134 of the CHRNA2 protein (p.Arg134Ser). This variant is present in population databases (rs773956983, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with CHRNA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 204989). 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 CHRNA2 protein function with a positive predictive value of 80%. 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. |