ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.728G>A (p.Arg243Gln) (rs62508588)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000089059 SCV000239068 pathogenic not provided 2018-10-04 criteria provided, single submitter clinical testing The R243Q missense variant in the PAH gene has been reported as a pathogenic variant in thePAH Consortium database. The R243Q variant isgenerally considered a severe PAH variant associated with a classic PKU phenotype; however, there are reports of thisvariant being associated with a mild PKU phenotype (Pey et al., 2003; Couce et al., 2013; Liang et al., 2014;Réblová et al., 2015). Therefore, genotype/phenotype predictions for the R243Q variant cannot be made at this time.R243Q is reported to be associated with approximately 10-18% residual phenylalanine hydroxylase activity comparedto wild-type (Shi et al., 2012; Couce et al., 2013; Liang et al., 2014). The R243Q variant is responsive to BH4therapy (Zurfluh et al. 2008). Missense variants in nearby residues (R241C, V245A, L249F) have been reported in theHuman Gene Mutation Database in association with PKU (Stenson et al., 2014), supporting the functionalimportance of this region of the protein. We interpret R243W as pathogenic.
Invitae RCV000000622 SCV000629211 pathogenic Phenylketonuria 2019-12-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 243 of the PAH protein (p.Arg243Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs62508588, ExAC 0.03%). This variant has been reported in the literature in multiple individuals affected with classic phenylketonuria (PKU), in homozygosis (PMID: 2071149, 27264808, 23716935, 24401910, 24705691), and as a compound heterozygote with other pathogenic variants (PMID: 23500595, 12655546). ClinVar contains an entry for this variant (Variation ID: 591). Experimental studies have shown that this missense change causes a drastic reduction in enzyme activity in vitro (PMID: 21953985, 23500595, 12655546). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000089059 SCV000700317 pathogenic not provided 2017-02-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000624337 SCV000742983 pathogenic Inborn genetic diseases 2016-01-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Fulgent Genetics,Fulgent Genetics RCV000000622 SCV000893946 pathogenic Phenylketonuria 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000000622 SCV000919909 pathogenic Phenylketonuria 2017-11-03 criteria provided, single submitter clinical testing Variant summary: The PAH c.728G>A (p.Arg243Gln) variant located in the aromatic amino acid hydroxylase, C-terminal (InterPro) involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 19/245876 control chromosomes at a frequency of 0.0000773, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). The variant of interest has been reported in multiple publications in affected compound heterozygote and homozygote individuals presenting with classic PKU, mild PKU, HPA, and mild-HPA. Activity levels for these affected individuals were indicated to have been significantly reduced in comparison to wild type (Aldamiz-Echevarria_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000089059 SCV001134524 pathogenic not provided 2018-10-31 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. Located in potentially important domain of the protein. 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.
Baylor Genetics RCV000000622 SCV001163720 pathogenic Phenylketonuria criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000089059 SCV001249182 pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
OMIM RCV000000622 SCV000020772 pathogenic Phenylketonuria 1992-05-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089059 SCV000119665 not provided not provided no assertion provided not provided
Counsyl RCV000000622 SCV000485299 pathogenic Phenylketonuria 2016-01-22 no assertion criteria provided clinical testing
Biochemistry Laboratory of CDMU,Chengde Medical University RCV000000622 SCV000899205 pathogenic Phenylketonuria no assertion criteria provided case-control

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