Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000590560 | SCV004222620 | pathogenic | Phenylketonuria | 2023-10-15 | reviewed by expert panel | curation | The NM_000277.3(PAH):c.226G>T (p.Glu76Ter) is a nonsense variant in exon 3/13 of PAH, and is predicted to result in PTC with removal of >10% of the protein and NMD (PVS1). The variant is absent from population databases, including gnomAD, ExAC, 1000 Genomes, or ESP (PM2_supporting). The variant has been previously reported in a patient with classic PKU (plasma Phe >1200 uM) (PMID: 17096675) with BH4 deficiency not noted to have been formally excluded (PP4), in cis with the c.1089delG variant (ClinVar Pathogenic, see ID 102518). In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PP4. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000590560 | SCV000696444 | likely pathogenic | Phenylketonuria | 2016-10-14 | criteria provided, single submitter | clinical testing | Variant summary: The PAH c.226G>T (p.Glu76X) variant results in a premature termination codon, predicted to cause a truncated or absent PAH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 121374 control chromosomes and has been reported in one HPA patient with c.1089delG in cis (Daniele_2006). c.1089delG has been reported as a frequent pathogenic variant in PKU and HPA patients. No patient with c.226G>T in separation has been reported. Taken together, this variant is classified as likely pathogenic. |