ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.781C>T (p.Arg261Ter) (rs5030850)

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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 RCV000000641 SCV000852174 pathogenic Phenylketonuria 2018-08-05 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PP4: Detected in 2 unrelated patients (PMID:1682234); PM3: Detected with H170D, pathogenic (PMID:11385716). 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, PP4, PM3).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000089090 SCV000232040 pathogenic not provided 2015-02-23 criteria provided, single submitter clinical testing
GeneDx RCV000089090 SCV000581840 pathogenic not provided 2017-05-04 criteria provided, single submitter clinical testing The R261X nonsense variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. An individual homozygous for theR261X variant was reported to have classic phenylketonuria (PKU) (Couce et al., 2013). Functionalanalysis found that R261X is associated with significantly reduced enzyme activity (Zurfluh et al.,2008; Ho et al., 2013). The R261X variant is classified as not responsive to tetrahydrobiopterin(BH4) therapy (Zurfluh et al., 2008). This variant is predicted to cause loss of normal proteinfunction through protein truncation. We interpret R261X as pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000000641 SCV000919918 pathogenic Phenylketonuria 2018-08-03 criteria provided, single submitter clinical testing Variant summary: PAH c.781C>T (p.Arg261X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.2e-05 in 277050 control chromosomes. c.781C>T has been reported in the literature in numerous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Zurfluh_2008). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000000641 SCV001215251 pathogenic Phenylketonuria 2019-12-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg261*) in the PAH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs5030850, ExAC 0.001%). This variant has been observed in many individuals and families affected with PAH-related conditions (PMID: 30067850). ClinVar contains an entry for this variant (Variation ID: 610). Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000089090 SCV001249181 pathogenic not provided 2019-01-01 criteria provided, single submitter clinical testing
OMIM RCV000000641 SCV000020791 pathogenic Phenylketonuria 1991-10-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089090 SCV000119696 not provided not provided no assertion provided not provided
Counsyl RCV000000641 SCV000485311 pathogenic Phenylketonuria 2016-01-21 no assertion criteria provided clinical testing

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