ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.527G>T (p.Arg176Leu) (rs74486803)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000088974 SCV000281654 pathogenic not provided 2016-05-03 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000088974 SCV000333001 pathogenic not provided 2015-07-30 criteria provided, single submitter clinical testing
GeneDx RCV000088974 SCV000490678 pathogenic not provided 2015-11-06 criteria provided, single submitter clinical testing The R167H variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. The R176L pathogenic variant is considered a mild PAH variant as it is associated with significant residual phenylalanine hydroxylase enzyme activity and has been described in association with mild and moderate phenylketonuria (PKU) and hyperphenylalaninemia (HPA) (Zurfluh et al., 2008; Couce et al., 2013; Guldberg et al., 1994). R176L is reported to be a tetrahydrobiopterin-responsive variant (Zurfluh et al., 2008). Therefore, we interpret R167H in PAH as a pathogenic variant.
Invitae RCV000346024 SCV000629199 pathogenic Phenylketonuria 2019-07-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 176 of the PAH protein (p.Arg176Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs74486803, ExAC 0.02%). This variant has been reported in several individuals affected with hyperphenylalaninemia, in an individual with mild phenylketonuria and in an individual with classical phenylketonuria (PMID: 8088845, 23500595, 27121329). This variant has been classified as BH4-responsive (PMID: 15464430, 17935162, 23500595). ClinVar contains an entry for this variant (Variation ID: 631). Experimental studies have shown that this missense variant reduces the enzymatic activity of PAH in vitro (PMID: 17924342, 27121329). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000000663 SCV000696454 pathogenic Hyperphenylalaninemia, non-pku 2017-08-22 criteria provided, single submitter clinical testing Variant summary: The PAH c.527G>T (p.Arg176Leu) variant located in the aromatic amino acid hydroxylase, C-terminal domain (via InterPro) involves the alteration of a non-conserved nucleotide and 3/4 in silico tools (Mutation Taster not captured due to low p-value) predict a damaging outcome for this variant. This variant was found in 15/276880 control chromosomes at a frequency of 0.0000542, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). Multiple publications cite the variant in mild-HPA patients as compound heterozygotes with an relative residual PAH activity level of 42% (Aldamiz-Echevarria_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000346024 SCV000893950 pathogenic Phenylketonuria 2018-10-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV000346024 SCV001163723 likely pathogenic Phenylketonuria criteria provided, single submitter clinical testing
OMIM RCV000000663 SCV000020813 pathogenic Hyperphenylalaninemia, non-pku 1994-05-15 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088974 SCV000119577 not provided not provided no assertion provided not provided
Counsyl RCV000346024 SCV000790017 pathogenic Phenylketonuria 2017-03-06 no assertion criteria provided clinical testing

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