ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.117C>G (p.Phe39Leu) (rs62642926)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078504 SCV000110360 pathogenic not provided 2016-08-08 criteria provided, single submitter clinical testing
GeneDx RCV000078504 SCV000239057 pathogenic not provided 2018-12-05 criteria provided, single submitter clinical testing The F39L missense variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. The F39L variant has been reported in individuals with classic phenylketonuria (PKU) who were also heterozygous for another variant in the PAH gene (Forrest et al., 1991; Jeannesson-Thivisol et al., 2015). BH4 responsiveness is inconsistent in individuals who harbor the F39L variant (Zurfluh et al., 2008; Ho et al., 2014; Jeannesson-Thivisol et al., 2015; Aldámiz-Echevarría et al., 2016). In summary, we interpret F39L as pathogenic.
Illumina Clinical Services Laboratory,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.
Invitae RCV000000636 SCV000629175 pathogenic Phenylketonuria 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 39 of the PAH protein (p.Phe39Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs62642926, ExAC 0.02%). This variant has been reported in individuals affected with classical phenylketonuria, mild phenylketonuria and hyperphenylalaninemia. It has been reported as a common cause of the disease in Scotland and Northern Ireland, although it has also been reported in many other populations (PMID: 8592329, 8659548, 12655544, 12655553, 17935162, 2063869). ClinVar contains an entry for this variant (Variation ID: 605). Experimental studies have shown that this missense change reduces PAH stability and its affinity for BH4 (PMID: 1146119, 15557004, 17935162, 21953985, 25563416). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America 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 criteria provided, single submitter clinical testing
Myriad Women's Health, 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).
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

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