ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1315+1G>T (rs5030861)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000410802 SCV001370876 likely pathogenic Phenylketonuria 2020-05-18 reviewed by expert panel curation The c.1315+1G>T variant in PAH is a canonical splice-site variant predicted to lead to skipping of exon 13 (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. It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). The variant has been previously reported in one Catalonian PKU case (as determined by abnormal blood Phe levels), without additional information (PMID: 10598814) (PP4). It is also noted in ClinVar (ID 370074), where it is classified as Likely Pathogenic by one lab, with this published reported cited. Classification: Likely Pathogenic Supporting Criteria: PVS1_Strong; PM2; PP4
Counsyl RCV000410802 SCV000485252 likely pathogenic Phenylketonuria 2015-11-27 criteria provided, single submitter clinical testing

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