ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1247C>A (p.Pro416Gln)

dbSNP: rs1445893088
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000674315 SCV001572867 likely pathogenic Phenylketonuria 2021-03-12 reviewed by expert panel curation The c.1247C>A (p.Pro416Gln) variant in PAH has been reported in 2 patients with mild PKU (PP4; PMID: 27413125, 31623983). This variant has been detected with pathogenic variants: p.I306V (PMID: 23430547) and c.664_665del (PMID: 17502162) (PM3). This variant has an extremely low frequency in gnomAD (MAF=0.000008792, PM2), and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.986 (PP3). This variant was shown to retain enzyme activity, but unfolds at a faster rate than WT (PMID: 18937047). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4.
Counsyl RCV000674315 SCV000799631 uncertain significance Phenylketonuria 2018-05-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000674315 SCV001577485 pathogenic Phenylketonuria 2024-08-02 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 416 of the PAH protein (p.Pro416Gln). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 18937047, 23430547; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 558091). 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 expected to disrupt PAH protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PAH function (PMID: 18937047). For these reasons, this variant has been classified as Pathogenic.

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