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

dbSNP: rs5030847

Total submissions: 17

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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000614	SCV000629214	pathogenic	Phenylketonuria	2024-12-02	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; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 584). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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	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	2024-03-09	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003984797	SCV004801190	pathogenic	Pulmonary hypertension, primary, 1	2024-03-14	criteria provided, single submitter	research
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