Submissions for variant NM_000277.3(PAH):c.117C>G (p.Phe39Leu)

gnomAD frequency: 0.00009  dbSNP: rs62642926

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000636	SCV001762340	pathogenic	Phenylketonuria	2020-03-27	reviewed by expert panel	curation	The c.117C>G (p.Phe39Leu) variant in PAH has been reported in multiple individuals with PKU. (PMID: 23430918, 8659548, 8406445, 2063869). This variant has an extremely low allele frequency in ExAC, gnomAD, 1000 Genomes, ESP (MAF=0.00016). This variant was detected with multiple pathogenic variants: T81P, V177L (PMID: 8659548), F55fsdelT (2 patients, PMID: 15557004), p.I65T, p.R408W (4 patients), p.R252W, p.E280K, c.1066-11G>A, c.1315+1G>A (PMID: 23430918). There is cosegregation with disease in affected siblings in 2 families PMID: 2063869, 8592329). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4, PP1.
Eurofins Ntd Llc (ga)	RCV000078504	SCV000110360	pathogenic	not provided	2016-08-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000078504	SCV000239057	pathogenic	not provided	2022-04-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Tetrahydrobiopterin (BH4) responsiveness is inconsistent in individuals who harbor the F39L variant (Zurfluh et al., 2008; Ho et al., 2014; Jeannesson-Thivisol et al., 2015; Aldmiz-Echevarra et al., 2016); This variant is associated with the following publications: (PMID: 11461190, 21953985, 27121329, 27760515, 8659548, 12655544, 23559577, 2063869, 25087612, 16338627, 29102225, 10429004, 8592329, 23430918, 25563416, 1146119, 12655553, 30037505, 15557004, 26666653, 24368688, 29030855, 30648773, 32853555, 32668217, 32778825, 33465300, 17935162, 27535533)
Illumina Laboratory Services, Illumina	RCV000000636	SCV000375571	pathogenic	Phenylketonuria	2017-04-27	criteria provided, single submitter	clinical testing	The PAH c.117C>G (p.Phe39Leu) missense variant is well-described in the literature and has been identified individuals with varying phenotypes, ranging from classic phenylketonuria (PKU) to untreated hyperphenylalaninemia with normal intelligence (Forrest et al. 1991; Tyfield et al. 1995; Kayaalp 1997). Across a selection of the available literature the p.Phe39Leu variant has been reported in a compound heterozygous state in at least seven patients and in at least 101 of 1738 patient alleles where zygosity was not specified (Forrest et al. 1991; Guldberg et al. 1993; Tyfield et al. 1995; Zschocke et al. 1995; O'Donnell et al. 2002; Erlandsen et al. 2004; Zurflüh et al 2008; Polak et al. 2013). The p.Phe39Leu variant is more common in Scottish and Northern Irish PKU populations, with a frequency of approximately 6% and 9.5% respectively (Tyfield et al., 1995; Zschocke et al., 1995). In vitro functional analysis by Waters et al. (1999 and 2000) revealed that the variant is associated with increased protein aggregation and accelerated proteolytic degradation compared to wild type, as well as partial conversion of normal oligomeric protein forms to higher molecular weight aggregates. The p.Phe39Leu variant was absent from at least 236 controls and is reported at a frequency of 0.00013 in the European (non-Finnish) population of the Exome Aggregation Consortium. The variant is generally described as a BH4-responsive variant (Erlandsen et al. 2004; Zurflüh et al. 2008; Heintz et al. 2012). Based on the collective evidence, the p.Phe39Leu 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000636	SCV000629175	pathogenic	Phenylketonuria	2024-01-22	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 39 of the PAH protein (p.Phe39Leu). This variant is present in population databases (rs62642926, gnomAD 0.02%). This missense change has been observed in individual(s) with phenylketonuria, mild phenylketonuria and hyperphenylalaninemia (PMID: 2063869, 8592329, 8659548, 12655544, 12655553, 17935162). It is commonly reported in individuals of Scotland and Northern Ireland ancestry (PMID: 2063869, 8592329, 8659548, 12655544, 12655553, 17935162). ClinVar contains an entry for this variant (Variation ID: 605). 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: 1146119, 15557004, 17935162, 21953985, 25563416). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000636	SCV000696429	pathogenic	Phenylketonuria	2017-02-16	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.117C>G (p.Phe39Leu) variant located in the ACT domain (via InterPro) involves the alteration of 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 11/121396 (1/11037), which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. Multiple publications have cited the variant in homozygous and compound heterozygous affected individuals. Publications have indicated that the variant causes a mild-moderate phenotype. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000078504	SCV000889562	pathogenic	not provided	2017-09-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000000636	SCV001163354	pathogenic	Phenylketonuria	2024-03-27	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000000636	SCV001194131	pathogenic	Phenylketonuria	2019-12-20	criteria provided, single submitter	clinical testing	NM_000277.1(PAH):c.117C>G(F39L) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 8592329, 21953985, 10429004, 24368688, 26666653, and 12173030. Classification of NM_000277.1(PAH):c.117C>G(F39L) 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.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000000636	SCV001251475	pathogenic	Phenylketonuria		criteria provided, single submitter	research	The PAH c.117C>G (p.F39L) missense variant has been reported in individuals with affected with phenylketonuria (PKU), mild PKU and hyperphenylalaninemia (PMID: 8592329; 8533759; 8659548; 12655553; 15557004).
Revvity Omics, Revvity	RCV000000636	SCV002016488	pathogenic	Phenylketonuria	2021-03-10	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000078504	SCV002064483	pathogenic	not provided	2017-11-29	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000000636	SCV002761795	pathogenic	Phenylketonuria	2022-01-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000000636	SCV002794910	pathogenic	Phenylketonuria	2022-04-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004018527	SCV004998564	pathogenic	Inborn genetic diseases	2023-12-06	criteria provided, single submitter	clinical testing	The c.117C>G (p.F39L) alteration is located in exon 2 (coding exon 2) of the PAH gene. This alteration results from a C to G substitution at nucleotide position 117, causing the phenylalanine (F) at amino acid position 39 to be replaced by a leucine (L). Based on data from gnomAD, the G allele has an overall frequency of 0.009% (26/282820) total alleles studied. The highest observed frequency was 0.016% (21/129140) of European (non-Finnish) alleles. This variant has been reported homozygous or with a second variant in PAH in multiple individuals diagnosed with phenylalanine hydroxylase deficiency (Forrest, 1991; Tyfield, 1995; Koch, 2005; Ho, 2014; Bayat, 2016; Ferreira, 2021). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000078504	SCV005042118	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	PAH: PM3:Very Strong, PM2, PP4:Moderate, PP1
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000000636	SCV005200805	pathogenic	Phenylketonuria	2024-05-20	criteria provided, single submitter	clinical testing	PM3_very-strong, PM2, PP4, PP1
OMIM	RCV000000636	SCV000020786	pathogenic	Phenylketonuria	1991-07-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000078504	SCV000119365	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000000636	SCV001459230	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003904791	SCV004719079	pathogenic	PAH-related disorder	2024-07-30	no assertion criteria provided	clinical testing	The PAH c.117C>G variant is predicted to result in the amino acid substitution p.Phe39Leu. This variant is documented as causative for phenylalanine hydroxylase deficiency, when found in the homozygous or compound heterozygous state (e.g., Guldberg et al. 1996. PubMed ID: 8659548; Sarkissian et al. 2012. PubMed ID: 23430918; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653; Table S3 in Hillert et al. 2020. PubMed ID: 32668217). In functional studies, the p.Phe39Leu amino acid change has been reported to result in reduced PAH protein levels as well as reduced enzyme activity (Zurflüh et al. 2008. PubMed ID: 17935162; Shi et al. 2012. PubMed ID: 21953985). Data regarding the responsiveness of patients with the p.Phe39Leu amino acid substitution to tetrahydrobiopterin (BH4) is conflicting (Zurflüh et al. 2008. PubMed ID: 17935162; Sarkissian et al. 2012. PubMed ID: 23430918). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It has been interpreted as pathogenic by the ClinGen PAH Variant Curation Expert Panel as well as numerous outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/605). This variant is interpreted as pathogenic.