Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000150081 | SCV001370847 | likely pathogenic | Phenylketonuria | 2020-02-23 | reviewed by expert panel | curation | The c.974A>G (p.Tyr325Cys) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). It was detected with pathogenic/LP variants p.L194P (LP) PMID: 23430918 L348V (P) PMID: 10679941 p.P281L (LP) PMID: 22526846 p.R408W (P) with parental analysis not reported for 1.5 points. This variant has extremely low frequency in gnomAD (MAF=0.00001). Computational evidence supports a a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. |
Eurofins Ntd Llc |
RCV000078541 | SCV000110397 | pathogenic | not provided | 2012-08-14 | criteria provided, single submitter | clinical testing | |
Counsyl | RCV000150081 | SCV000796739 | likely pathogenic | Phenylketonuria | 2017-12-28 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000150081 | SCV000822786 | pathogenic | Phenylketonuria | 2023-08-17 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 10679941, 32668217; BIOPKU http://www.biopku.org). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 325 of the PAH protein (p.Tyr325Cys). This variant is present in population databases (rs62508578, gnomAD 0.0009%). ClinVar contains an entry for this variant (Variation ID: 92756). 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. For these reasons, this variant has been classified as Pathogenic. |
De |
RCV000078541 | SCV000119802 | not provided | not provided | no assertion provided | not provided | ||
Natera, |
RCV000150081 | SCV002088636 | likely pathogenic | Phenylketonuria | 2020-09-14 | no assertion criteria provided | clinical testing |