ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.896T>G (p.Phe299Cys) (rs62642933)

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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 RCV000089148 SCV000232506 pathogenic not provided 2015-01-08 criteria provided, single submitter clinical testing
GeneDx RCV000089148 SCV000239077 pathogenic not provided 2018-11-08 criteria provided, single submitter clinical testing The F299C variant in the PAH gene has been reported as a pathogenic variant in the PAH ConsortiumDatabase. The F299C missense variant has been reported previously inassociation with phenylketonuria (PKU) (Eiken et al., 1992; Jeannesson-Thivisol et al., 2015).Functional analysis of F299C found that it is associated with significantly reduced enzyme activity anda patient homozygous for F299C was described as having severe PKU (Knappskog et al., 1993; Waterset al., 1998; Eiken et al., 1992). It is currently unknown if F299C is responsive to tetrahydrobiopterin(BH4) therapy (Jeannesson-Thivisol et al., 2015).
Invitae RCV000000644 SCV000754080 pathogenic Phenylketonuria 2019-11-10 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with cysteine at codon 299 of the PAH protein (p.Phe299Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is present in population databases (rs62642933, ExAC 0.02%). This variant has been reported as homozygous or in combination with other pathogenic PAH variants in several individuals affected with hyperphenylalaninemia and phenylketonuria. This variant has been described as a common cause of the disease in Norway and the British Islands, although it has also been observed in other populations (PMID: 7726156, 8831077, 9012412, 9781015, 12173030, 1312992, 26666653). ClinVar contains an entry for this variant (Variation ID: 613). Experimental studies have shown that this missense change abrogates PAH enzymatic activity in vitro (PMID: 8304187). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000000644 SCV000893939 pathogenic Phenylketonuria 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000000644 SCV000915569 pathogenic Phenylketonuria 2018-08-14 criteria provided, single submitter clinical testing The PAH c.896T>G (p.Phe299Cys) missense variant has been reported in at least six studies and identified in 12 individuals with phenylketonuria (PKU) or hyperphenylalaninemia (HPA) including in one individual with the variant in a homozygous state and 11 individuals in a compound heterozygous state (Eiken et al. 1992; Waters et al. 1998; Aulehla-Scholz and Heilbronner 2003). The variant was also identified in ten alleles where zygosity was not specified in individuals with classical PKU or HPA (Zschoke et al. 1995; Kozák et al. 1997). Control data are unavailable for the p.Phe299Cys variant which is reported at a frequency of 0.000349 in the European American population of the Exome Sequencing Project. Carter et al. (1998) also report the variant at an average frequency of 6.4% in newborns with PKU or non-PKU HPA identified through newborn screening in Quebec. Based on the evidence, the p.Phe299Cys 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000089148 SCV001134526 pathogenic not provided 2019-02-01 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000000644 SCV001251470 pathogenic Phenylketonuria criteria provided, single submitter research The PAH c.896T>G (p.F299C) missense variant has been reported in the homozygous or compound heterozygous state in multiple individuals with phenylketonuria (PMID: 8659548; 12655553; 1312992).
Integrated Genetics/Laboratory Corporation of America RCV000000644 SCV001362285 pathogenic Phenylketonuria 2019-05-16 criteria provided, single submitter clinical testing Variant summary: PAH c.896T>G (p.Phe299Cys) results in a non-conservative amino acid change located in the Eukaryotic phenylalanine-4-hydroxylase, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251056 control chromosomes. c.896T>G has been reported in the literature in numerous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). These data indicate that the variant is very likely to be associated with disease. The variant is reported to have 0% in vitro enzyme activity (Eiken_1996). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000000644 SCV000020794 pathogenic Phenylketonuria 1992-03-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089148 SCV000119760 not provided not provided no assertion provided not provided
Counsyl RCV000000644 SCV000220607 pathogenic Phenylketonuria 2016-07-18 no assertion criteria provided clinical testing

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