Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000993614 | SCV001146731 | likely pathogenic | Phenylketonuria | 2019-04-07 | reviewed by expert panel | curation | The c.493G>A (p.Ala165Thr) variant in PAH has been reported in multiple individuals with PKU, including siblings (BH4 deficiency excluded). (PP4_Moderate, PMID: 8981952; PP1, PMID: 26666653). This variant has extremely low frequency in gnomAD (MAF=0.00001) (PM2). This variant was detected with c.1066-11G>A (PM3; PMID: 10598814). Multiple lines of computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP1, PP3. |
Labcorp Genetics |
RCV000993614 | SCV003003779 | pathogenic | Phenylketonuria | 2024-06-29 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 165 of the PAH protein (p.Ala165Thr). This variant is present in population databases (rs199475626, gnomAD 0.0009%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 26666653). ClinVar contains an entry for this variant (Variation ID: 102700). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. |
De |
RCV000088948 | SCV000119549 | not provided | not provided | no assertion provided | not provided |