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

gnomAD frequency: 0.00004  dbSNP: rs5030846

Total submissions: 18

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).
Eurofins Ntd Llc (ga)	RCV000078528	SCV000110384	pathogenic	not provided	2013-06-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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	2019-12-05	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Patients homozygous for the R243X variant are reported to have a classic PKU phenotype and are not responsive to BH4 therapy (Zurfluh et al., 2008); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 26589311, 26210745, 30747360, 26655635, 23500595, 11486900, 24941924, 24130151, 17935162, 26759449, 27121329, 14741196, 2309142, 2014036, 28676969, 28540274, 29499199, 31355225, 26666653, 31589614)
Invitae	RCV000000619	SCV000629210	pathogenic	Phenylketonuria	2024-01-14	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. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs5030846, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with PKU (PMID: 2014036, 11486900, 14741196, 17935162, 23500595, 24130151, 26666653; Invitae). ClinVar contains an entry for this variant (Variation ID: 588). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
CeGaT Center for Human Genetics Tuebingen	RCV000078528	SCV001370957	pathogenic	not provided	2020-05-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000000619	SCV001810548	pathogenic	Phenylketonuria	2021-07-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002512610	SCV003696594	pathogenic	Inborn genetic diseases	2021-04-20	criteria provided, single submitter	clinical testing	The c.727C>T (p.R243*) alteration, located in exon 7 (coding exon 7) of the PAH gene, consists of a C to T substitution at nucleotide position 727. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 243. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This mutation has been reported in multiple homozygous and compound heterozygous individuals with phenylalanine hydroxylase deficiency (Zare-Karizi, 2011; Couce, 2013; Ald&aacute;miz-Echevarr&iacute;a, 2016; Su, 2019). Based on the available evidence, this alteration is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003407250	SCV004114446	pathogenic	PAH-related condition	2023-08-23	criteria provided, single submitter	clinical testing	The PAH c.727C>T variant is predicted to result in premature protein termination (p.Arg243*). This sequence variant has been reported to be causative phenylalanine hydroxylase deficiency and has been associated with classical phenylketonuria (PKU) (e.g., Okano et al. 1991. PubMed ID: 2014036; Couce et al. 2013. PubMed ID: 23500595; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653). Patients with the c.727C>T variant have been reported to be non-responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). Nearly one hundred patients homozygous for the c.727C>T (p.Arg243*) variant have been reported in the BioPKU database; all of these patients presented with classic PKU (http://www.biopku.org). In the ClinVar database, this variant is classified as pathogenic by the ClinGen PAH Variant Curation Expert Panel as well as multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/588/). Nonsense variants in PAH are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic.
Baylor Genetics	RCV000000619	SCV004201323	pathogenic	Phenylketonuria	2023-10-29	criteria provided, single submitter	clinical testing
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
Natera, Inc.	RCV000000619	SCV001453113	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000078528	SCV001926514	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078528	SCV001951335	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000078528	SCV001973072	pathogenic	not provided		no assertion criteria provided	clinical testing