Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000671113 | SCV002032212 | likely pathogenic | Phenylketonuria | 2021-07-17 | reviewed by expert panel | curation | The c.635T>C (p.Leu212Pro) variant in PAH has been reported in multiple individuals with PAH deficiency (PMID: 9781015) detected with pathogenic variants: p.R408W (PMID: 17502162); p.R158Q (PMID: 23430918); c.1066-11G>A (PMID: 26666653). This variant is absent in population databases. In vitro residual activity of the p.L212P mutant enzyme is 17% of wild type, and it also showed reduced protein expression. Computational prediction tools and conservation analysis support a deleterious effect on the protein. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3_supporting, PM2, PM3, PP3, PP4. |
| Counsyl | RCV000671113 | SCV000796058 | likely pathogenic | Phenylketonuria | 2017-11-28 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000671113 | SCV003441223 | pathogenic | Phenylketonuria | 2023-05-09 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 212 of the PAH protein (p.Leu212Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hyperphenylalaninemia (PMID: 32668217). ClinVar contains an entry for this variant (Variation ID: 102768). 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. Experimental studies have shown that this missense change affects PAH function (PMID: 27620137). For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000671113 | SCV003934425 | pathogenic | Phenylketonuria | 2023-05-28 | criteria provided, single submitter | clinical testing | Variant summary: PAH c.635T>C (p.Leu212Pro) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251336 control chromosomes. c.635T>C has been reported in the literature as biallelic genotypes in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Fisch_2004, Dobrowolski_2007, Sarkissian_2012, Jeannesson-Thivisol_2015, Hillert_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Trunzo_2016). The most pronounced variant effect results in 17% of normal PAH enzyme activity in vitro. The following publications have been ascertained in the context of this evaluation (PMID: 17502162, 15110327, 32668217, 26666653, 23430918, 27620137). Two clinical diagnostic laboratories and the ClinGen PAH Variant Curation Expert Panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV000671113 | SCV004209650 | likely pathogenic | Phenylketonuria | 2023-06-21 | criteria provided, single submitter | clinical testing | |
| De |
RCV000089018 | SCV000119622 | not provided | not provided | no assertion provided | not provided |