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

gnomAD frequency: 0.00001  dbSNP: rs62642944

Total submissions: 5

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)
Labcorp Genetics (formerly Invitae), Labcorp	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