Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000823427 | SCV001370812 | pathogenic | Phenylketonuria | 2020-05-09 | reviewed by expert panel | curation | The PAH variant c.799C>T (p.Gln267Ter) is a null variant (stop gain) located in exon number 7 of the PAH gene. Loss of function in the PAH gene is a mechanism of disease. Eleven null variants in exon 7 of the PAH gene have been reported. The mRNA transcript is predicted to undergo NMD. The variant c.799C>T (p.Gln267Ter) was reported in trans with the pathogenic PAH variant c.442-1G>A (ClinVar ID: 594) in a Chinese patient with classic PKU (Phe levels >20 mg/dl). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. (PMID: 26322415). The PAH variant c.799C>T (p.Gln267Ter) was also reported in trans with the pathogenic PAH variant IVS10-11G>A (ClinVar ID: 607) in a Brazilian patient with classic PKU (PMID: 18798839) PM3_Strong (2.0). The variant c.799C>T (p.Gln267Ter) is absent from the gnomAD, ExAC, PAGE, and ESP population databases. In summary, this variant meets the criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Strong, PVS1, PP4-moderate. |
| Labcorp Genetics |
RCV000823427 | SCV000964287 | pathogenic | Phenylketonuria | 2018-11-05 | criteria provided, single submitter | clinical testing | This variant has been observed in several individuals affected with PKU (PMID: 26322415, 18798839). This sequence change creates a premature translational stop signal (p.Gln267*) in the PAH gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic. |