Submissions for variant NM_000277.3(PAH):c.526C>T (p.Arg176Ter)

gnomAD frequency: 0.00003  dbSNP: rs199475575

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000179282	SCV000852175	pathogenic	Phenylketonuria	2018-08-13	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PM2: ExAC MAF: 0.00010; PP4_Moderate: BH4 defect excluded in all patients in Liu 2015. Identified in 6 patients in this study (PMID:10394930; PMID:26600521); PM3_Strong: Identified in 6 patients, in trans with R243Q and R241C (both pathogenic) (PMID:26600521). 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, PM3_Strong).
Eurofins Ntd Llc (ga)	RCV000088971	SCV000231507	pathogenic	not provided	2014-08-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000179282	SCV000629197	pathogenic	Phenylketonuria	2024-05-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg176*) 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 (rs199475575, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with phenyketonuria (PMID: 8268925, 17935162, 23514811, 26413448, 26503515). ClinVar contains an entry for this variant (Variation ID: 102723). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000179282	SCV000696453	pathogenic	Phenylketonuria	2016-03-03	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000179282	SCV000744099	pathogenic	Phenylketonuria	2014-10-08	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000179282	SCV000745573	pathogenic	Phenylketonuria	2016-07-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000088971	SCV000888349	pathogenic	not provided	2018-07-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000179282	SCV000893951	pathogenic	Phenylketonuria	2018-10-31	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000179282	SCV001810542	pathogenic	Phenylketonuria	2021-07-22	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000179282	SCV002573258	pathogenic	Phenylketonuria	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 26600521). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000102723 / PMID: 8268925). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000179282	SCV004201383	pathogenic	Phenylketonuria	2024-03-27	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000179282	SCV005418246	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing	PVS1+PM2_Supporting+PM3_VeryStrong
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088971	SCV000119574	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000179282	SCV000485295	pathogenic	Phenylketonuria	2016-01-21	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000179282	SCV001455097	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing