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

gnomAD frequency: 0.00006  dbSNP: rs62514952

Total submissions: 18

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	2021-09-02	criteria provided, single submitter	clinical testing	Reported in multiple patients with classic PKU, and one patient with mild PKU, in the presence of a second variant; also reported in a patient with classic PKU in the homozygous state (Svensson et al., 1990; Jeannesson-Thivisol et al., 2015; Williams et al., 2015); Associated with approximately 6%-7% residual activity compared to wild-type (Ho et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Classified as not responsive to BH4 therapy (Zurfluh et al. 2008); This variant is associated with the following publications: (PMID: 8444221, 10471838, 17935162, 22975760, 25525159, 23532445, 1975559, 25551302, 8889583, 29555771, 29431110, 31980526, 32668217, 33101986, 8188310, 32853555, 31589614, 26666653, 33375644, 27535533)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000627	SCV000754076	pathogenic	Phenylketonuria	2023-12-25	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. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs62514952, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with PKU (PMID: 1975559, 10471838). ClinVar contains an entry for this variant (Variation ID: 596). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000089110	SCV000888354	pathogenic	not provided	2018-05-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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 Genetics, 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).
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000089110	SCV001468124	pathogenic	not provided	2020-10-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000000627	SCV002016483	pathogenic	Phenylketonuria	2021-01-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000000627	SCV004209581	pathogenic	Phenylketonuria	2024-03-26	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000000627	SCV005051911	pathogenic	Phenylketonuria	2024-02-01	criteria provided, single submitter	curation
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
Natera, Inc.	RCV000000627	SCV001453102	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000089110	SCV001741618	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000089110	SCV001927778	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000089110	SCV001973806	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003914791	SCV004736008	pathogenic	PAH-related disorder	2024-02-13	no assertion criteria provided	clinical testing	The PAH c.814G>T variant is predicted to result in premature protein termination (p.Gly272*). This variant has been reported in the homozygous state or with a second pathogenic PAH variant in many patients with phenylalanine hydroxylase deficiency (for example, see Table S3 in Hillert A et al 2020. PubMed ID: 32668217). This variant and has been reported to essentially abolish PAH enzyme activity, and patients with this variant have been reported to be non-responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). (Zurflüh et al. 2008. PubMed ID: 17935162). In the homozygous state, the c.814G>T variant has been associated with classical phenylketonuria (PKU) (Ellingsen et al. 1999. PubMed ID: 10471838). The ClinGen PAH Curation Expert Panel and multiple other outside laboratories classify this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/596/). Nonsense variants in PAH are expected to be pathogenic. Based on these observations, we also interpret this variant as pathogenic.