ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.727C>T (p.Arg243Ter) (rs5030846)

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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 RCV000000619 SCV000852113 pathogenic Phenylketonuria 2018-08-07 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PVS1: nonsense variant; PS3: <1% of normal PAH activity (PMID:2014036). 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: (PVS1, PS3).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078528 SCV000110384 pathogenic not provided 2013-06-20 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000000619 SCV000375567 pathogenic Phenylketonuria 2017-04-27 criteria provided, single submitter clinical testing The PAH c.727C>T (p.Arg243Ter) variant is a stop gained variant that is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Arg243Ter variant has been identified in a total of 20 patients with phenylalanine hydroxylase deficiency leading to phenylketonuria, including in ten in a homozygous state and in ten in a compound heterozygous state (Wang et al. 1990; Ramus et al. 1993; Zurflüh et al. 2008; Zare-Karizi et al. 2011; Spaapen et al. 2011; Couce et al. 2013; Bashyam et al. 2014). Control data are unavailable for this variant from these studies, which is reported at a frequency of 0.00009 in the European (non-Finnish) population of the Exome Aggregation Consortium. Patients with the p.Arg243Ter variant showed reduced enzyme activity of < 1% of wild type (Zurflüh et al. 2008; Couce et al. 2013). Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg243Ter variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000078528 SCV000490681 pathogenic not provided 2016-11-25 criteria provided, single submitter clinical testing The R243X variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. The R243X pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Patients homozygous for the R243X variant are reported to have a classic phenylketonuria (PKU) phenotype and are not responsive to BH4 therapy (BIOPKU database; Zurfluh et al., 2008). Therefore, we interpret R243X as a pathogenic variant.
Invitae RCV000000619 SCV000629210 pathogenic Phenylketonuria 2020-01-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg243*) in the PAH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs5030846, ExAC 0.009%). This particular variant has been reported as homozygous or in combination with other PAH variants in multiple individuals affected with PKU (PMID: 14741196, 11486900, 2014036, 17935162, 23500595, 24130151, 26666653, Invitae). ClinVar contains an entry for this variant (Variation ID: 588). Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000000619 SCV000696462 pathogenic Phenylketonuria 2017-08-22 criteria provided, single submitter clinical testing Variant summary: The PAH c.727C>T (p.Arg243X) variant results in a premature termination codon, predicted to cause a truncated or absent PAH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One truncation downstream of this position has been classified as pathogenic by our laboratory (c.1089delG, p.Lys363fsX37). One in silico tool predicts a damaging outcome for this variant. A functional study found this variant to be associated with in vitro hydroxylase activity <1% of normal levels (Okano_1991). This variant was found in the large control database ExAC in 6/121162 control chromosomes at a frequency of 0.0000495, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant has been reported in many affected individuals with phenylketonuria and hyperphenylalaninemia (Zurfluh_2008, Couce_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
OMIM RCV000000619 SCV000020769 pathogenic Phenylketonuria 1991-03-15 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078528 SCV000119664 not provided not provided no assertion provided not provided
Counsyl RCV000000619 SCV001132445 pathogenic Phenylketonuria 2014-01-02 no assertion criteria provided clinical testing

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