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

gnomAD frequency: 0.00001  dbSNP: rs5030850

Total submissions: 20

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).
Eurofins Ntd Llc (ga)	RCV000089090	SCV000232040	pathogenic	not provided	2015-02-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000089090	SCV000581840	pathogenic	not provided	2020-11-17	criteria provided, single submitter	clinical testing	Functional analysis found that R261X is associated with significantly reduced enzyme activity (Zurflh et al., 2008; Ho et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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; Classified as not responsive to tetrahydrobiopterin (BH4) therapy (Zurflh et al., 2008); This variant is associated with the following publications: (PMID: 30747360, 25525159, 12655553, 10693064, 23500595, 17935162, 24401910, 1682234, 23532445, 28676969, 15503242, 19062537, 30067850, 29499199, 30221392, 31355225, 30275481, 31589614, 33101986)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000641	SCV001215251	pathogenic	Phenylketonuria	2024-10-12	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. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs5030850, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with PAH-related conditions (PMID: 30067850). ClinVar contains an entry for this variant (Variation ID: 610). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000089090	SCV001249181	pathogenic	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000000641	SCV001810236	pathogenic	Phenylketonuria	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000000641	SCV002016497	pathogenic	Phenylketonuria	2019-04-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000089090	SCV002046336	pathogenic	not provided	2020-11-12	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of PAH protein synthesis. In addition, it has been reported in multiple classic and mild PKU patients in the published literature (PMID: 16601866 (2006), 16755493 (2006), 19394257 (2009), 20920871 (2011), 22841515 (2012), 30067850 (2018)). Therefore, the variant is classified as pathogenic.
Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences	RCV000000641	SCV004035242	pathogenic	Phenylketonuria	2023-09-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000000641	SCV004209584	pathogenic	Phenylketonuria	2024-02-27	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003984798	SCV004801189	pathogenic	Pulmonary hypertension, primary, 1	2024-03-14	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000000641	SCV004848682	pathogenic	Phenylketonuria	2022-06-30	criteria provided, single submitter	clinical testing	The p.Arg261X variant in PAH has been reported in >20 individuals with phenylketonuria in the homozygous or compound heterozygous state (Dworniczak 1991 PMID: 1682234, Yang 2001 PMID: 11385716, Liang 2014 PMID: 24401910, Gundorova 2018 PMID: 30067850). It has also been identified in 0.004% (3/68014) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Pathogenic on Aug 05, 2018 by the ClinGen-approved PAH Variant Curation expert panel (Variation ID 610). In vitro functional studies support an impact on protein function and have shown 1% residual enzyme activity (Zurfluh 2008 PMID: 17935162). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive phenylketonuria. ACMG/AMP Criteria applied: PVS_1, PM3, PM2_P, PS3_P.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000000641	SCV005051902	pathogenic	Phenylketonuria	2024-02-01	criteria provided, single submitter	curation
Mayo Clinic Laboratories, Mayo Clinic	RCV000089090	SCV005414113	pathogenic	not provided	2024-01-30	criteria provided, single submitter	clinical testing	PM2, PM3, PS4, PVS1
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000000641	SCV005416884	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing	PM2+PVS1+PM3_VeryStrong+PP4
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
Natera, Inc.	RCV000000641	SCV001453106	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing