ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1318G>T (p.Glu440Ter)

dbSNP: rs1874485021
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV001200010 SCV001370867 likely pathogenic Phenylketonuria 2020-05-15 reviewed by expert panel curation The c.1318G>T (p.E440*) is a nonsense variant in exon 13 of 13 of PAH, a gene where loss of function is a known disease mechanism, and is predicted to lead to premature truncation of the protein at amino acid 440/453 (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 premature truncation 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 abnormal blood Phe (BH4 deficiency does not appear to have been formally excluded) (PP4) (PMID: 23842451), in presumed trans with the p.R243* mutation (Pathogenic per PAH VCEP) (0.5 points; PM3_Supporting). Classification: Likely Pathogenic Supporting Criteria: PVS1_Strong; PM2; PM3_Supporting; PP4

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