Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000672448 | SCV001762300 | pathogenic | Phenylketonuria | 2020-06-08 | reviewed by expert panel | curation | The c.1252A>C (p.Thr418Pro) variant in PAH has been reported in multiple individuals with mild and classic PKU (BH4 deficiency excluded). (PMID: 26503515). This variant has an extremely low allele frequency (MAF=0.00003) in gnomAD. It was detected in trans with multiple pathogenic variants: p.Arg243Gln, p.Arg408Gln, p.Arg176*, EX6-96A>G, p.Tyr356*, p.Arg111* (PMID: 28982351). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3. |
Counsyl | RCV000672448 | SCV000797554 | pathogenic | Phenylketonuria | 2018-02-06 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000672448 | SCV003441151 | pathogenic | Phenylketonuria | 2024-01-22 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 418 of the PAH protein (p.Thr418Pro). This variant is present in population databases (rs62644501, gnomAD 0.003%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 1301187, 26322415, 29499199, 29731766, 30747360, 31355225). ClinVar contains an entry for this variant (Variation ID: 102580). 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. |
Baylor Genetics | RCV000672448 | SCV005053810 | pathogenic | Phenylketonuria | 2024-03-19 | criteria provided, single submitter | clinical testing | |
De |
RCV000088818 | SCV000119409 | not provided | not provided | no assertion provided | not provided |