ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.814G>T (p.Gly272Ter) (rs62514952)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000000627 SCV000852120 pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. Extrememly low frequency in ExAC, gnomAD (MAF= 0.00006, 0.0003093); PVS1: Nonsense variant. Predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.; PP4: G272X found on one allele of a patient with classic PKU (PMID:1975559). 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: (PM2, PVS1, PP4).
GeneDx RCV000089110 SCV000239074 pathogenic not provided 2017-10-05 criteria provided, single submitter clinical testing The G272X nonsense variant has been reported in multiple patients with classific PKU, and one patient with mild PKU, in the presence of a second variant (Svensson et al., 1990; Jeannesson-Thivisol et al., 2015). The G272X variant has also been reported in a patient with classic PKU in the homozygous state (Williams et al., 2015). The G272X variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant is associated with less than 1% residual activity and is classified as not responsive to BH4 therapy (Zurfluh et al. 2008). In summary, we interpret G272X as pathogenic.
Invitae RCV000000627 SCV000754076 pathogenic Phenylketonuria 2019-11-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly272*) in the PAH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs62514952, ExAC 0.006%). This variant has been reported as homozygous or in combination with another PAH variant in individuals affected with PKU (PMID: 10471838, 1975559). ClinVar contains an entry for this variant (Variation ID: 596). Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000089110 SCV000888354 pathogenic not provided 2018-05-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000000627 SCV000919920 pathogenic Phenylketonuria 2018-08-31 criteria provided, single submitter clinical testing Variant summary: PAH c.814G>T (p.Gly272X) 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 5.1e-05 in 277088 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (5.1e-05 vs 0.0079), allowing no conclusion about variant significance. c.814G>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria)(Jeannesson-Thivisol_2015, Aldamiz-Echevarria_2016). These data indicate that the variant is very likely to be associated with disease. The variant was found to cause a loss of enzyme activity via functional studies (Aldamiz-Echevarria_2016). Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Women's Health, Inc. RCV000000627 SCV001194050 pathogenic Phenylketonuria 2019-12-09 criteria provided, single submitter clinical testing NM_000277.1(PAH):c.814G>T(G272*) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and is associated with the classic form of disease. Sources cited for classification include the following: PMID 1671881, 24350308, 1978553, 10471838, 1975559 and 12655550. Classification of NM_000277.1(PAH):c.814G>T(G272*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000000627 SCV001251473 pathogenic Phenylketonuria criteria provided, single submitter research The PAH c.814G>T (p.G272*) nonsense variant is predicted to result in premature termination of the PAH protein and/or nonsense-mediated decay. This variant has been previously reported as pathogenic in individuals with phenylketonuria (PMID: 8370573; 1975559; 1978553; 17935162; 10471838; 12655550).
OMIM RCV000000627 SCV000020777 pathogenic Phenylketonuria 1993-09-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089110 SCV000119717 not provided not provided no assertion provided not provided

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