Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000672958 | SCV001146743 | uncertain significance | Phenylketonuria | 2019-09-27 | reviewed by expert panel | curation | The c.637C>T (p.Leu213Phe) variant in PAH is the same amino acid change as an established pathogenic variant, c.638T>C (p.Leu213Pro) VarID:92747. (PM5). This variant is absent in population databases (PM2). This variant has not been reported in the literature to our knowledge. Multiple lines of computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as uncertain significance for PAH. |
| Gene |
RCV000493939 | SCV000583195 | likely pathogenic | not provided | 2017-05-26 | criteria provided, single submitter | clinical testing | The L213F substitution occurs at a position that is conserved across species.In silico analysis predicts this variant is probably damaging to the protein structure/function. Amissense variant at the same residue (L213P) has been reported in the Human Gene MutationDatabase in association with PKU (Stenson et al., 2014), supporting the functional importance of thisregion of the protein. In summary, we interpret L213F to be likely pathogenic. |
| Invitae | RCV000672958 | SCV003034535 | likely pathogenic | Phenylketonuria | 2022-02-25 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 213 of the PAH protein (p.Leu213Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PAH-related conditions. ClinVar contains an entry for this variant (Variation ID: 430401). 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.Leu213 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8632937, 9521426, 19292873, 22112818, 23430547). 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. |
| Counsyl | RCV000672958 | SCV000798118 | uncertain significance | Phenylketonuria | 2018-02-26 | no assertion criteria provided | clinical testing |