ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs76296470
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Total submissions: 16
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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

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