Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000700598 | SCV000829358 | uncertain significance | Autosomal dominant nocturnal frontal lobe epilepsy | 2019-12-30 | 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. A different missense substitution at this codon (p.Ser280Phe) has been determined to be pathogenic (PMID: 22036597, 7550350). This suggests that the serine residue is critical for CHRNA4 protein function and that other missense substitutions at this position may also be pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CHRNA4-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with cysteine at codon 280 of the CHRNA4 protein (p.Ser280Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. |