ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.789C>G (p.Phe263Leu)

gnomAD frequency: 0.00001  dbSNP: rs62642944
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000758091 SCV000886556 uncertain significance Phenylketonuria 2018-12-10 reviewed by expert panel curation The c.789C>G (p.Phe263Leu) variant in PAH is reported in 1 patient with classical PKU, and 1 Chinese PKU patient. (BH4 deficiency excluded. PMID: 8222245, 26600521) This variant is absent from 1000G and ESP with extremely low frequency in ExAC/gnomAD (MAF=0.00003). It is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.929. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PP3.
GeneDx RCV000089092 SCV001780298 pathogenic not provided 2019-12-06 criteria provided, single submitter clinical testing Reported previously in association with phenylalanine hydroxylase deficiency (Takarada et al., 1993; Liu et al., 2015; Reblova et al., 2013); Published functional studies demonstrate a damaging effect with 5% residual PAH activity compared to wild-type (Lagler et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32668217, 26600521, 20705059, 7844888, 23357515, 8222245)
Invitae RCV000758091 SCV003441155 pathogenic Phenylketonuria 2023-12-20 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 263 of the PAH protein (p.Phe263Leu). This variant is present in population databases (rs62642944, gnomAD 0.003%). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 7844888, 8222245, 26600521, 32668217). 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: 102833). 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%. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000758091 SCV004209611 pathogenic Phenylketonuria 2023-08-23 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089092 SCV000119699 not provided not provided no assertion provided not provided

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