Submissions for variant NM_000277.3(PAH):c.165T>G (p.Phe55Leu)

gnomAD frequency: 0.00023  dbSNP: rs199475598

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078512	SCV000110368	pathogenic	not provided	2012-08-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000150092	SCV000611224	likely pathogenic	Phenylketonuria	2021-11-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588067	SCV000696440	pathogenic	Hyperphenylalaninemia	2016-12-30	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.165T>G (p.Phe55Leu) variant located in the ACT domain causes a missense change involving a conserved nucleotide, which 3/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 11/121376 (1/11037), which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. The variant of interest has been reported in multiple affected individuals diagnosed with HPA as compound heterozygotes. In addition, multiple databases and clinical diagnostic laboratories have cited the variant with a classification of "pathogenic" or "likely pathogenic." Therefore, the variant of interest has been classified as "Pathogenic."
Labcorp Genetics (formerly Invitae), Labcorp	RCV000150092	SCV000827978	pathogenic	Phenylketonuria	2024-01-29	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 55 of the PAH protein (p.Phe55Leu). This variant is present in population databases (rs199475598, gnomAD 0.09%). This missense change has been observed in individual(s) with hyperphenylalaninemia or phenylketonuria (PMID: 9298832, 9521426, 10598814, 12501224, 18299955, 23932990). ClinVar contains an entry for this variant (Variation ID: 92734). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 18538294). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000150092	SCV000914560	pathogenic	Phenylketonuria	2018-10-31	criteria provided, single submitter	clinical testing	The PAH c.165T>G (p.Phe55Leu) missense variant has been reported in over nine studies and is found in at least twelve probands in a compound heterozygous state (Zekanowski et al. 1997; Bosco et al. 1998; Guldberg et al. 1998; Zekanowski et al. 2001; Muntau et al. 2002; Aulehla-Scholz et al. 2003; Bercovoch et al. 2008; Sarkissan et al. 2010; Zhu et al. 2013). The p.Phe55Leu variant was absent from 320 controls and is reported at a frequency of 0.00093 in the Latino population of the Genome Aggregation Database. Functional studies by Gertsing et al. (2008) demonstrated that the Phe55 residue is part of the hydrophobic core of the regulatory domain of the protein. The variant showed only a moderate reduction in enzyme activity compared to wild type and was shown to induce misfolding and facilitate unfolding but did not affect the conformational stability of the catalytic domain. Based on the evidence, the p.Phe55Leu variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Myriad Genetics, Inc.	RCV000150092	SCV001194100	pathogenic	Phenylketonuria	2019-12-20	criteria provided, single submitter	clinical testing	NM_000277.1(PAH):c.165T>G(F55L) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 30367646, 27121329, 26655635, 9298832, 18538294, 18299955, 11678552, 23932990, 23430918 and 9521426. Classification of NM_000277.1(PAH):c.165T>G(F55L) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Genome-Nilou Lab	RCV000150092	SCV001810549	likely pathogenic	Phenylketonuria	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000150092	SCV002016482	pathogenic	Phenylketonuria	2021-03-06	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251964	SCV002523847	pathogenic	See cases	2020-11-13	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PS4, PM3, PP1, PP3, PP4
3billion	RCV000150092	SCV002572851	pathogenic	Phenylketonuria	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.016%). It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.85; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000092734). A different missense change at the same codon (p.Phe55Ser) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000120266). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
CeGaT Center for Human Genetics Tuebingen	RCV000078512	SCV004131792	pathogenic	not provided	2023-02-01	criteria provided, single submitter	clinical testing	PAH: PM3:Very Strong, PM2, PS3:Supporting
Baylor Genetics	RCV000150092	SCV004201328	pathogenic	Phenylketonuria	2024-03-30	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150092	SCV004848752	pathogenic	Phenylketonuria	2022-08-26	criteria provided, single submitter	clinical testing	The c.165T>G (p.Phe55Leu) variant in PAH has been reported in at least 27 individuals with phenylalanine hydroxylase deficiency/phenylketonuria (PKU)/hyperphenylalaninemia (HPA) (Zhu 2013 PMID: 23932990, Zekanowski PMID: 9298832,Vela-Amieva 2021 PMID: 34828281, Ozturk 2022 PMID: 35405047, Ferreira 2021 PMID: 33465300, Bosco 1998 PMID: 9521426, Bercovich 2008 PMID: 1829995, Aldamiz-Echevarria 2016 PMID: 27121329), and at least 12 of these individuals were compound heterozygous for a second pathogenic PAH variant. It has been identified in 0.002% of AMR chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID: 92734). Computational prediction tools suggest that this variant may impact the protein, though this information is not predictive enough to to determine pathogenecity. In vitro functional studies support an impact of p.Arg155His on protein function (Gersting S, et al. 2008 PMID: 18538294). This variant occurs in exon 2 of PAH where numerous pathogenic variants in PAH have been identified, including at the same residue (p.Phe55Ser). In summary, c.165T>G (p.Phe55Leu) meets criteria to be classified as pathogenic for autosomal recessive PKU. ACMG/AMP Criteria applied: PM3_VeryStrong, PM5_Strong, PM2_Supporting, PP3, PS3_Supporting.
Mayo Clinic Laboratories, Mayo Clinic	RCV000078512	SCV005414125	pathogenic	not provided	2024-03-19	criteria provided, single submitter	clinical testing	PP3, PP4, PM3_very_strong
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000078512	SCV000119438	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000150092	SCV001459228	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739340	SCV005357669	pathogenic	PAH-related disorder	2024-08-01	no assertion criteria provided	clinical testing	The PAH c.165T>G variant is predicted to result in the amino acid substitution p.Phe55Leu. This variant has previously been reported, in the compound heterozygous state with a second causative variant, in multiple patients with hyperphenylalaninemia (e.g., Zekanowski et al. 1997. PubMed ID: 9298832; Bosco et al. 1998. PubMed ID: 9521426; Aldámiz-Echevarría et al. 2016. PubMed ID: 27121329; Table S3, Hillert et al. 2020. PubMed ID: 32668217). In functional studies, the p.Phe55Leu substitution was reported to affect protein allostery and proteolytic stability (Gersting et al. 2008. PubMed ID: 18538294). This variant is typically associated with mild hyperphenylalaninemia or mild phenylketonuria (PKU) (Table S2, Hillert et al. 2020. PubMed ID: 32668217). This variant is classified as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/92734/). Taken together, we classify this variant as pathogenic.