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

gnomAD frequency: 0.00001  dbSNP: rs62507336

Total submissions: 15

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	2021-12-06	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; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Classified as non-responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh et al., 2008); This variant is associated with the following publications: (PMID: 25525159, 8268925, 26600521, 8830172, 15503242, 9012412, 23430918, 23932990, 24368688, 9634518, 17502162, 17096675, 12655553, 31589614, 32778825, 29316886, 29749107, 30829006, 17935162)
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000169529	SCV000744098	pathogenic	Phenylketonuria	2014-10-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169529	SCV000959031	pathogenic	Phenylketonuria	2025-01-13	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. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs62507336, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with phenylketonuria (PMID: 8830172, 26600521). ClinVar contains an entry for this variant (Variation ID: 102736). 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.
Revvity Omics, Revvity	RCV000169529	SCV003822315	pathogenic	Phenylketonuria	2021-12-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169529	SCV004201374	pathogenic	Phenylketonuria	2023-12-19	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000088985	SCV005414119	pathogenic	not provided	2023-10-17	criteria provided, single submitter	clinical testing	PP4, PM2_moderate, PM3, PS3, PVS1
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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000088985	SCV001956805	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000088985	SCV001971621	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739364	SCV005351623	pathogenic	PAH-related disorder	2024-06-28	no assertion criteria provided	clinical testing	The PAH c.561G>A variant is predicted to result in premature protein termination (p.Trp187*). This variant has been reported to be causative for phenylalanine hydroxylase deficiency (for example, see Guldberg et al. 1993. PubMed: 8268925; Romano et al. 1996. PubMed: 8830172; Ho et al. 2014. PubMed ID: 24368688; Hillert et al. 2020. PubMed ID: 32668217).This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is interpreted as pathogenic or likely pathogenic by multiple submitters to ClinVar, including the ClinGen PAH Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/102736/). Nonsense variants in PAH are expected to be pathogenic. This variant is interpreted as pathogenic.