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

Total submissions: 10

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