Total submissions: 16
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Eurofins Ntd Llc |
RCV000089148 | SCV000232506 | pathogenic | not provided | 2015-01-08 | criteria provided, single submitter | clinical testing | |
Gene |
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) |
Labcorp Genetics |
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, |
RCV000000644 | SCV000893939 | pathogenic | Phenylketonuria | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Illumina Laboratory Services, |
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 | 2024-02-25 | criteria provided, single submitter | clinical testing | The PAH c.896T>G (p.Phe299Cys) variant has been reported in the published literature in individuals with classic Phenylketonuria (PMID: 9634518 (1998), 10980574 (2000), 26666653 (2015), 32668217 (2020)) and hyperphenylalaninemia (PMID: 8533759 (1995), 12173030 (2002)). This variant has been reported to cause severely reduced PAH residual activity (PMIDs: 9399896 (1997) and 10980574 (2000)). The frequency of this variant in the general population, 0.00019 (25/128870 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Please note that these prediction tools are not fully validated, and therefore, should be viewed with caution. Based on the available information, this variant is classified as pathogenic. Genetic counseling and testing of at-risk relatives are recommended. |
UNC Molecular Genetics Laboratory, |
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, |
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. |
Ce |
RCV000089148 | SCV004010187 | pathogenic | not provided | 2024-04-01 | criteria provided, single submitter | clinical testing | PAH: PM3:Very Strong, PM2, PP4:Moderate, PP3, PS3:Supporting |
Baylor Genetics | RCV000000644 | SCV004201360 | pathogenic | Phenylketonuria | 2024-03-27 | criteria provided, single submitter | clinical testing | |
Mayo Clinic Laboratories, |
RCV000089148 | SCV005414108 | pathogenic | not provided | 2024-07-08 | criteria provided, single submitter | clinical testing | PP3, PP4, PM2_moderate, PM3_very_strong |
OMIM | RCV000000644 | SCV000020794 | pathogenic | Phenylketonuria | 1992-03-01 | no assertion criteria provided | literature only | |
De |
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, |
RCV000000644 | SCV001463135 | pathogenic | Phenylketonuria | 2020-09-16 | no assertion criteria provided | clinical testing | |
Prevention |
RCV004739275 | SCV005360671 | pathogenic | PAH-related disorder | 2024-03-23 | no assertion criteria provided | clinical testing | The PAH c.896T>G variant is predicted to result in the amino acid substitution p.Phe299Cys. This variant has been recurrently reported in the homozygous state or in the heterozygous state with a second PAH variant in individuals with phenylalanine hydroxylase deficiency (e.g., Eiken et al. 1996. PubMed ID: 8875186; Carter et al. 1998. PubMed ID: 9781015; Hillert et al. 2020. PubMed ID: 32668217). It has been reported to reduce enzyme activity to <3% in an in vitro study, and is considered to be a classic phenylketonuria (PKU) variant (Knappskog et al. 1993. PubMed ID: 8304187; http://www.biopku.org/pah/result-details-pah.asp?ID=341#). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic. |