Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000672872 | SCV001762335 | likely pathogenic | Phenylketonuria | 2021-07-25 | reviewed by expert panel | curation | The c.1074A>T (p.Leu358Phe) variant in PAH meets criteria to be classified as likely pathogenic. PAH-specific ACMG/AMP criteria applied: PM2: Variant is present at low frequency in gnomAD (0.0000) and ExAC (0.00002). Absent from 1000 Genomes. PM3: Found to co-occur with F331S in one patient with mild HPA, but no additional studies to demonstrate phase of variants (PMID: 23764561). Found to co-occur with other non-PKU HPA mutation I306V, phase was not confirmed (PMID: 23357515). Found to co-occur in two patients with L348V and R408W with mild and classic PKU, respectively. (PMID: 24350308) PP3: Predicted to be damaging (SIFT), probably damaging (PolyPhen2), Disease causing (MutationTaster). PP4: In both studies, patients were recruited for their abnormal Phelevels defined as HPA <600umol or 120-600umol. There was no additional testing done to rule out other similar analyte disorders. PS3_Not Met: Functional studies in E. Coli model used and relative specific activity of L358F is 52+-0.7%, which is above our 50% threshold to apply this line of evidence. |
Counsyl | RCV000672872 | SCV000798020 | uncertain significance | Phenylketonuria | 2018-02-22 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000672872 | SCV000940771 | pathogenic | Phenylketonuria | 2023-05-27 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PAH function (PMID: 28653649). 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. ClinVar contains an entry for this variant (Variation ID: 556817). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 23357515, 23764561, 24350308; Invitae). This variant is present in population databases (rs376480977, gnomAD 0.002%). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 358 of the PAH protein (p.Leu358Phe). |
Fulgent Genetics, |
RCV000672872 | SCV002797772 | pathogenic | Phenylketonuria | 2022-04-07 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV000672872 | SCV004209604 | pathogenic | Phenylketonuria | 2023-08-30 | criteria provided, single submitter | clinical testing |