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

gnomAD frequency: 0.00007  dbSNP: rs62642933

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000089148	SCV000232506	pathogenic	not provided	2015-01-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000089148	SCV000239077	pathogenic	not provided	2020-02-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, specifically that F299C mutant protein is associated with significantly reduced enzyme activity (Knappskog et al., 1993; Waters et al., 1998); Individuals with classic PKU who harbored F299C and a second variant in PAH were described as non-responsive to tetrahydrobiopterin (BH4) therapy (Jeannesson-Thivisol et al., 2015); This variant is associated with the following publications: (PMID: 11368310, 9399896, 9781015, 8889590, 9642259, 15597538, 24517888, 24368688, 12655547, 8831077, 1971147, 8533759, 7913581, 12655553, 8304187, 17924342, 25087612, 10980574, 19244369, 9391881, 26666653, 9450897, 1312992, 32668217, 32853555)
Invitae	RCV000000644	SCV000754080	pathogenic	Phenylketonuria	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 299 of the PAH protein (p.Phe299Cys). This variant is present in population databases (rs62642933, gnomAD 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). 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%. Experimental studies have shown that this missense change affects PAH function (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 Laboratory Services, 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
CeGaT Center for Human Genetics Tuebingen	RCV000089148	SCV004010187	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	PAH: PM3:Strong, PM2, PP4:Moderate, PP3, PS3:Supporting
Baylor Genetics	RCV000000644	SCV004201360	pathogenic	Phenylketonuria	2023-10-18	criteria provided, single submitter	clinical testing
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
Natera, Inc.	RCV000000644	SCV001463135	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing