Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000850224 | SCV001370839 | likely pathogenic | Phenylketonuria | 2020-06-26 | reviewed by expert panel | curation | The c.1102G>A (p.Glu368Lys) variant in PAH has been reported in 1 individual with moderate PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 31355225). This variant has extremely low frequency in gnomAD: MAF=0.00001 (PM2). This variant was detected in trans with pathogenic variant c.1066-11G>A. Parents were also investigated to confirm their carrier status. (PM3). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3. |
Labcorp Genetics |
RCV000850224 | SCV003786582 | pathogenic | Phenylketonuria | 2023-11-21 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 368 of the PAH protein (p.Glu368Lys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 31355225). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 625289). 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%. For these reasons, this variant has been classified as Pathogenic. |
Center for Molecular Medicine, |
RCV000850224 | SCV000893130 | pathogenic | Phenylketonuria | 2019-03-08 | no assertion criteria provided | clinical testing |