Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000186923 | SCV000240494 | uncertain significance | not provided | 2018-01-25 | criteria provided, single submitter | clinical testing | p.Pro169Arg (CCC>CGC): c.506 C>G in exon 5 of the CHRNA4 gene (NM_000744.5)The Pro169Arg missense change 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 non-conservative amino acid substitution of an uncharged Proline residue with a positively charged Arginine residue at a position that is conserved across species. Additionally, the removal of a Proline residue, which has a unique ring structure, may alter the secondary structure of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether Pro169Arg is a disease-causing mutation or a rare benign variant. The variant is found in CHILD-EPI panel(s). |
Invitae | RCV002304203 | SCV002591857 | uncertain significance | Autosomal dominant nocturnal frontal lobe epilepsy | 2022-09-21 | criteria provided, single submitter | clinical testing | 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) performed at Invitae indicates that this missense variant is expected to disrupt CHRNA4 protein function. This variant has not been reported in the literature in individuals affected with CHRNA4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 169 of the CHRNA4 protein (p.Pro169Arg). |