ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.473G>A (p.Arg158Gln) (rs5030843)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000000618 SCV000852101 pathogenic Phenylketonuria 2018-08-05 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PS3: R158Q is associated with very low levels (0.2-1.8%) of pah enzyme activity compared to wild-type. (PMID:2014036; PMID:19036622); PP3: tools predict damaging ; PP4_Moderate: BH4 testing showed responsive in a pt, pretreatment 1065uM (PMID:23500595); PM3_VeryStrong: in trans with 4 pathogenic variants: I48S, c.1315+1G>A, P281L, R261Ter. (PMID:23500595; PMID:10479481; PMID:24368688). 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: (PS3, PP3, PP4_Moderate, PM3_VeryStrong).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078522 SCV000110378 pathogenic not provided 2016-10-26 criteria provided, single submitter clinical testing
GeneDx RCV000078522 SCV000239054 pathogenic not provided 2019-01-09 criteria provided, single submitter clinical testing The R158Q missense variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. The R158Q variant has beenreported as a severe", "mild-severe" and "mild" variant (Pey et al., 2007). Functional analysis ofR158Q found that it is associated with significantly reduced enzyme activity compared to wild type(Steventon et al., 2009). BH4 responsiveness has been inconsistent in patients with R158Q (Zurfluh etal., 2008)."
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078522 SCV000601714 pathogenic not provided 2017-06-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000000618 SCV000611233 pathogenic Phenylketonuria 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000000618 SCV000629193 pathogenic Phenylketonuria 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 158 of the PAH protein (p.Arg158Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs5030843, ExAC 0.02%). This is a prevalent mutation in the European population which has been reported in multiple individuals affected with PKU (PMID: 2014036, 25596310, 23500595, 10479481, 10479481, 24368688). ClinVar contains an entry for this variant (Variation ID: 587). Experimental studies have shown that this missense change impairs enzyme activity in vitro (PMID: 19036622, 14654665). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000000618 SCV000696450 pathogenic Phenylketonuria 2016-07-28 criteria provided, single submitter clinical testing Variant summary: The PAH c.473G>A (p.Arg158Gln) variant involves the alteration of a conserved nucleotide. The affected amino acid, Arg158, is located in the Aromatic amino acid hydroxylase, C-terminal domain. 4/5 in silico tools predict a damaging outcome for this variant, and the residual activity from in vitro cell based assays was reported to be 10% of wild type activity (Zurfluh_HM_2008 and BIOPKU database). This variant was found in 12/121256 control chromosomes at a frequency of 0.000099, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant has been reported in numerous patients with classic or moderate PKU. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000000618 SCV000746356 pathogenic Phenylketonuria 2017-12-03 criteria provided, single submitter clinical testing
Baylor Genetics RCV000000618 SCV001163725 pathogenic Phenylketonuria criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000000618 SCV001193837 pathogenic Phenylketonuria 2019-12-09 criteria provided, single submitter clinical testing NM_000277.1(PAH):c.473G>A(R158Q) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and is associated with classic or variant PKU. Sources cited for classification include the following: PMID 22513348, 2014036, 2606484, 12655546, 19036622, 21953985 and 17935162. Classification of NM_000277.1(PAH):c.473G>A(R158Q) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
OMIM RCV000000618 SCV000020768 pathogenic Phenylketonuria 1989-12-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078522 SCV000119542 not provided not provided no assertion provided not provided
GeneReviews RCV000000618 SCV000324887 pathogenic Phenylketonuria 2016-10-20 no assertion criteria provided literature only

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