ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1314_1315+4del (rs1334974448)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000671688 SCV001370866 pathogenic Phenylketonuria 2020-05-21 reviewed by expert panel curation The c.1314_1315+4del6 (p.N438fs) variant is a frameshift variant in exon 12 of 13 of a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (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 is listed in ClinVar (variant ID 555797) as Likely Pathogenic by one lab. It has been reported in the published literature in one case (PMID: 23514811) with abnormal blood Phe and BH4 deficiency formally excluded (PP4_Moderate); in trans with the p.R138Q variant (Pathogenic per PAH VCEP) (PM3). Classification: Pathogenic Supporting Criteria: PVS1_Strong; PM2; PM3; PP4_Moderate
Counsyl RCV000671688 SCV000796688 likely pathogenic Phenylketonuria 2017-12-21 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.