Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002005780 | SCV002273832 | likely pathogenic | Phenylketonuria | 2021-10-12 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with serine at codon 241 of the PAH protein (p.Arg241Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with PAH-related conditions. 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 PAH protein function. This variant disrupts the p.Arg241 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10479481, 22330942, 25894915, 26600521). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |