ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.561G>A (p.Trp187Ter) (rs62507336)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000169529 SCV000852146 pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PM2: Extremely low frequency in gnomAD. MAF=0.00002.; PP4_Moderate: Detected in 3 chromosomes of patients with PAH deficiency. BH4 deficiency ruled out. (PMID:8268925). 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, PM2, PP4_Moderate).
Counsyl RCV000169529 SCV000221006 likely pathogenic Phenylketonuria 2015-01-06 criteria provided, single submitter literature only
GeneDx RCV000088985 SCV000680747 pathogenic not provided 2017-12-27 criteria provided, single submitter clinical testing The W187X variant in the PAH gene has been reported in association with phenylalanine hydroxylase deficiency (Liu et al., 2015; Romano et al., 1996) and has been reported as homozygous in an individual with classic phenylketonuria (PKU) (Romano et al., 1996). The W187X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This nonsense variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The W187X variant has been associated tetrahydrobiopterin (BH4) unresponsiveness (Zurflüh et al., 2008). In summary, we interpret W187X as a pathogenic variant.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000169529 SCV000744098 pathogenic Phenylketonuria 2014-10-08 criteria provided, single submitter clinical testing
Invitae RCV000169529 SCV000959031 pathogenic Phenylketonuria 2020-07-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp187*) in the PAH gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous or in combination with another PAH variant in individuals affected with phenylketonuria (PMID: 8830172, 26600521). ClinVar contains an entry for this variant (Variation ID: 102736). Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169529 SCV001442683 pathogenic Phenylketonuria 2020-10-04 criteria provided, single submitter clinical testing Variant summary: PAH c.561G>A (p.Trp187X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251296 control chromosomes. c.561G>A has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Guldberg_1993, Guldberg_1996, Liu_2015). These data indicate that the variant is 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 (example, Guldberg_1996). Three clinical diagnostic laboratories and one expert panel (Clingen) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088985 SCV000119589 not provided not provided no assertion provided not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000169529 SCV000733125 pathogenic Phenylketonuria no assertion criteria provided clinical testing
Natera, Inc. RCV000169529 SCV001455092 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000088985 SCV001956805 pathogenic not provided no assertion criteria provided clinical testing

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