Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001200009 | SCV001370865 | likely pathogenic | Phenylketonuria | 2020-05-18 | reviewed by expert panel | curation | The c.1306delT (p.S436Pfs*16) variant in PAH is a frameshift variant in exon 12 of 13 of a gene where LOF is a known mechanism of disease, leading to premature truncation (PVS1_Strong). Exon 13 encodes 15 amino acids + stop codon = 3.3% of PAH protein length. Along with Exon 12, Exon 13 forms the oligomerization domain (residues 411-452), which is responsible for the dimerization and tetramerization of the enzyme, important for regulation of PAH activity (e.g., positive cooperativity by the substrate, L-Phe, and decreasing PAH activity at low L-Phe concentration) (see PMID: 23457044; PMID: 22005392). Exon 13 contains the non-truncating Likely Pathogenic p.A447P (Likely Pathogenic by ClinGen PAH VCEP) and Pathogenic p.A447D variants (Likely Pathogenic by ClinGen PAH VCEP; Pathogenic in Clinvar (ID 102595; 4 submitters, 2 stars). Thus PVS1_Strong will be applied for variants resulting in deletion of this exon. The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been previously reported in one proband with classic PKU, as indexed by abnormal blood Phe levels and in whom BH4 deficiency was said to excluded (PP4_Moderate); it was found in presumed trans with the IVS10-11G>A variant (Pathogenic per ClinGen PAH VCEP) (PMID: 18299955) (0.5 points total; PM3_Supporting). Classification: Likely Pathogenic Supporting Criteria: PVS1_Strong, PM2; PP4_Moderate; PM3_Supporting |