Submissions for variant NM_000277.3(PAH):c.331C>T (p.Arg111Ter)

gnomAD frequency: 0.00004  dbSNP: rs76296470

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000611	SCV000852165	pathogenic	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PP4_Moderate: Seen in multiple Chinese PKU patients. BH4 deficiency excluded. (PMID:1301187; PMID:2816939; PMID:9860305); PM3: Detected with R243Q, pathogenic in ClinVar (PMID:15503242). 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_Moderate, PM3).
Eurofins Ntd Llc (ga)	RCV000088898	SCV000228838	pathogenic	not provided	2015-02-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000611	SCV000629190	pathogenic	Phenylketonuria	2025-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg111*) 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 (rs76296470, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with phenylketonuria (PMID: 12542580, 16256386, 21307867, 24401910, 27121329). ClinVar contains an entry for this variant (Variation ID: 581). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000000611	SCV000893952	pathogenic	Phenylketonuria	2022-03-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000611	SCV000919917	pathogenic	Phenylketonuria	2018-08-03	criteria provided, single submitter	clinical testing	Variant summary: PAH c.331C>T (p.Arg111X) 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 3.2e-05 in 246200 control chromosomes (gnomAD). The variant, c.331C>T, has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria)(Tao_2015, Tyfield_1995). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000000611	SCV002016473	pathogenic	Phenylketonuria	2020-11-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000000611	SCV004201372	pathogenic	Phenylketonuria	2024-03-26	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000088898	SCV005414123	pathogenic	not provided	2023-08-07	criteria provided, single submitter	clinical testing	PM2_moderate, PVS1
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000000611	SCV005415688	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PM3_VeryStrong
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000088898	SCV005624691	pathogenic	not provided	2024-07-12	criteria provided, single submitter	clinical testing	The PAH c.331C>T (p.Arg111*) variant (also known as R111X) causes the premature termination of PAH protein synthesis. In the published literature, this variant has been reported in many individuals affected with phenylketonuria (PKU) (PMIDs: 17935162 (2008), 24401910 (2014), 29288420 (2018), 29413232 (2018), 36104584 (2022), and Gundorova et al. 2019 Russ J Genet 55:1025). The frequency of this variant in the general population, 0.000035 (4/113714 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
OMIM	RCV000000611	SCV000020761	pathogenic	Phenylketonuria	1990-05-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088898	SCV000119496	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000000611	SCV000485304	pathogenic	Phenylketonuria	2016-01-21	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000000611	SCV001455111	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000088898	SCV001931381	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000088898	SCV001959189	pathogenic	not provided		no assertion criteria provided	clinical testing