Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000672945 | SCV004015301 | pathogenic | Phenylketonuria | 2021-02-13 | reviewed by expert panel | curation | The c.1144T>C (p.Phe382Leu) variant in PAH has been reported in 1 homozygous individual with mild HPA and BH4 deficiency excluded (PP4_Moderate; 0.5 points; PMID: 21147011) and has also been reported in a patient from southern Italy (PMID: 17096675; PMID: 18346471) with mild hyperphenylalanemia (serum Phe 182 umol/L; not specified if BH4 deficiency excluded), who harbored it in presumed trans with the p.R252W variant (Pathogenic in ClinVar by 10 submitters, variation ID 584) (0.5 points) (PM3, 1 point total). This variant was absent in population databases (PM2). Expressed in COS-1 cells, this variant has 18% enzyme activity (PS3; PMID: 22698810). Computational prediction tools suggest that the variant may impact the protein (REVEL = 0.89; PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3, PM2, PM3, PP4_moderate, PP3. |
| Counsyl | RCV000672945 | SCV000798102 | uncertain significance | Phenylketonuria | 2018-02-28 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000672945 | SCV002301456 | pathogenic | Phenylketonuria | 2024-02-19 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 382 of the PAH protein (p.Phe382Leu). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 21147011). ClinVar contains an entry for this variant (Variation ID: 556882). 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%. Experimental studies have shown that this missense change affects PAH function (PMID: 22698810). Studies have shown that this missense change results in skipping of exon 11 and introduces a premature termination codon (PMID: 22698810). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. |