Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001199987 | SCV001370822 | uncertain significance | Phenylketonuria | 2020-03-27 | reviewed by expert panel | curation | The c.1264G>A (p.Glu422Lys) variant in PAH has been reported in 1 individual with PKU (BH4 deficiency excluded; PP4_Moderate; PMID: 31737040). This variant is absent from population databases (PM2). This variant is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.96 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. |
Labcorp Genetics |
RCV001199987 | SCV003441000 | uncertain significance | Phenylketonuria | 2022-09-28 | 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 422 of the PAH protein (p.Glu422Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 10541324, 31737040; Invitae). 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: 102583). 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. 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. |
De |
RCV000088821 | SCV000119412 | not provided | not provided | no assertion provided | not provided |