ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.754C>T (p.Arg252Trp) (rs5030847)

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Total submissions: 9
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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 2016-04-26 criteria provided, single submitter clinical testing The R252W missense variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. The R252W variant mutation is classified as a severe PAH variant associated with no phenylalanine hydroxylase activity and a classic phenylketonuria (PKU) phenotype (Pey et al., 2007). R252W is not responsive to BH4 (Zurfluh et al., 2008).
Invitae RCV000000614 SCV000629214 pathogenic Phenylketonuria 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 252 of the PAH protein (p.Arg252Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs5030847, ExAC 0.009%). This variant has been reported as homozygous or compound heterozygous in multiple individuals affected with PAH-associated diseases with evidence of segregation (PMID: 2574153, 17096675, 25596310, 20082265, 8116675, Invitae). ClinVar contains an entry for this variant (Variation ID: 584). Experimental studies have shown that this variant causes loss of enzyme activity in vitro (PMID: 25596310, 12655546). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000089079 SCV000700469 pathogenic not provided 2017-11-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
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

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