Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003316903 | SCV004015325 | uncertain significance | Phenylketonuria | 2023-03-16 | reviewed by expert panel | curation | The c.229T>C (p.Tyr77His) variant in PAH is a missense variant predicted to cause substitution of tyrosine by histidine at amino acid 77. It has been detected in 1 patient with mild PKU with second variant not reported (PMID: 27469133). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant is classified as uncertain significance due to insufficient evidence for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PP3, PP4. |
| Labcorp Genetics |
RCV003316903 | SCV004296187 | uncertain significance | Phenylketonuria | 2024-01-14 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 77 of the PAH protein (p.Tyr77His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hyperphenylalaninemia (PMID: 27469133; Invitae). ClinVar contains an entry for this variant (Variation ID: 2573214). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |