ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.754C>T (p.Arg252Trp)

dbSNP: rs5030847
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000000614 SCV000852089 pathogenic Phenylketonuria 2018-08-13 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: gnomAD MAF: 0.00006; PP3: tools predict damaging ; PS3: 1% residual activity (PMID:25596310; PMID:17935162); PP4: Detection of codon 252arg>trp in a patient with PAH deficiency (PMID:2574153); PM3: Detected with IVS10-11G>A, R261Q, IVS12+1, R68S (all P/LP). (PMID:18299955; PMID:11524738). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PP4, PM3).
GeneDx RCV000089079 SCV000239071 pathogenic not provided 2021-08-04 criteria provided, single submitter clinical testing Classified as a severe variant and reported as homozygous and in the presence of a second PAH pathogenic variant in individuals with classic PKU (Ajami et al., 2003; Desviat et al., 2001; Aulehla-Scholz et al., 2003); Published functional studies demonstrates R252W results in no detectable PAH activity (Pey et al., 2003; Danecka et al., 2015); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Classified as not responsive to BH4 therapy (Zurfluh et al., 2008; Danecka et al., 2015); This variant is associated with the following publications: (PMID: 12655546, 12655553, 17935162, 27535533, 31589614, 1672294, 22513348, 31355225, 30963030, 30037505, 29499199, 9825986, 18294361, 20920871, 11524738, 24301756, 24350308, 23792259, 8304187, 18299955, 8533759, 11461196, 8831077, 10693064, 27264808, 23500595, 2574153, 25750018, 21953985, 25596310, 22975760, 25087612)
Invitae RCV000000614 SCV000629214 pathogenic Phenylketonuria 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 252 of the PAH protein (p.Arg252Trp). This variant is present in population databases (rs5030847, gnomAD 0.006%). This missense change has been observed in individuals with PAH-associated diseases (PMID: 2574153, 8116675, 17096675, 20082265, 25596310; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 584). 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: 12655546, 25596310). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga) RCV000089079 SCV000700469 pathogenic not provided 2017-11-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000000614 SCV000917921 pathogenic Phenylketonuria 2018-04-26 criteria provided, single submitter clinical testing Variant summary: PAH c.754C>T (p.Arg252Trp) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal 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 4.9e-05 in 121328 control chromosomes (ExAC). This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (4.9e-05 vs 0.0079), allowing no conclusion about variant significance. The variant, c.754C>T, has been reported in the literature in numerous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) in both the compound heterozygous and homozygous states (Aldmiz-Echevarra_2016, Dobrowolski_2011, Jeannesson-Thivisol_2015) and enzyme activity has been reported in patients as <10% of normal activity. Three 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000089079 SCV001134525 pathogenic not provided 2018-11-27 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. One other pathogenic or likely pathogenic variant affects the same amino acid. 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.
Revvity Omics, Revvity Omics RCV000000614 SCV002016485 pathogenic Phenylketonuria 2021-06-21 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002251844 SCV002523268 pathogenic See cases 2019-10-04 criteria provided, single submitter clinical testing ACMG classification criteria: PS3, PM2, PM3
Fulgent Genetics, Fulgent Genetics RCV000000614 SCV002806583 pathogenic Phenylketonuria 2021-07-15 criteria provided, single submitter clinical testing
Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences RCV000000614 SCV004035234 pathogenic Phenylketonuria 2023-09-19 criteria provided, single submitter clinical testing
Baylor Genetics RCV000000614 SCV004209582 pathogenic Phenylketonuria 2023-09-18 criteria provided, single submitter clinical testing
OMIM RCV000000614 SCV000020764 pathogenic Phenylketonuria 1994-01-15 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089079 SCV000119685 not provided not provided no assertion provided not provided
Counsyl RCV000000614 SCV000220747 pathogenic Phenylketonuria 2016-01-21 no assertion criteria provided clinical testing
Natera, Inc. RCV000000614 SCV001453108 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing
Laboratory of Medical Genetics, University of Torino RCV000000614 SCV001547478 pathogenic Phenylketonuria 2021-03-10 no assertion criteria provided research

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