Total submissions: 14
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000000634 | SCV000852097 | pathogenic | Phenylketonuria | 2018-08-05 | reviewed by expert panel | curation | The c.829T>G (p.Tyr277Asp) variant in PAH has been reported in 2 individuals with Classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 8268925; PMID: 23500595). This variant has an extremely low allele frequency (1/121400) in ExAC (PM2; http://exac.broadinstitute.org). This variant has 0% enzyme activity (PS3; http://www.biopku.org/centralStore/biopku/PAH%20activity.pdf). This variant was detected in trans with L48S (Pathogenic in ClinVar) (PM3; PMID: 23500595). Computational prediction tools and conservation analysis suggest that the c.829T>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3 |
Eurofins Ntd Llc |
RCV000078531 | SCV000110387 | pathogenic | not provided | 2014-05-15 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000078531 | SCV000239075 | pathogenic | not provided | 2020-10-05 | criteria provided, single submitter | clinical testing | Reported previously in association with both classic and moderate phenylketonuria (Labrune et al., 1991; Couce et al., 2013; Aldamiz-Echevarria et al., 2016); Functional studies in COS cells showed no residual enzyme activity compared to wild-type (Pey et al., 2003); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Response to BH4 therapy is inconsistent (Couce et al., 2013; Jeannesson-Thivisol et al., 2015; Aldamiz-Echevarria et al., 2016); This variant is associated with the following publications: (PMID: 18346471, 27413125, 12655546, 21953985, 25882749, 23500595, 27121329, 26666653, 2035532, 30037505, 31980526, 31589614, 32668217) |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000078531 | SCV000601718 | pathogenic | not provided | 2016-10-05 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000000634 | SCV000834704 | pathogenic | Phenylketonuria | 2024-01-27 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 277 of the PAH protein (p.Tyr277Asp). This variant is present in population databases (rs78655458, gnomAD 0.003%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 2035532, 8268925, 8632937, 12173030, 12655546, 23500595, 26666653). This variant is also known as c.754C>T. ClinVar contains an entry for this variant (Variation ID: 603). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 12655546). For these reasons, this variant has been classified as Pathogenic. |
Fulgent Genetics, |
RCV000000634 | SCV000893942 | pathogenic | Phenylketonuria | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000000634 | SCV000919910 | pathogenic | Phenylketonuria | 2017-09-05 | criteria provided, single submitter | clinical testing | Variant summary: The PAH c.829T>G (p.Tyr277Asp) variant involves the alteration of a conserved nucleotide located in the Aromatic amino acid hydroxylase, C-terminal domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/121400 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). The variant has been reported in numerous affected individuals in the literature in the homozygous and compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. |
Revvity Omics, |
RCV000000634 | SCV002016479 | pathogenic | Phenylketonuria | 2021-11-10 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV000000634 | SCV004209656 | pathogenic | Phenylketonuria | 2024-02-06 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000000634 | SCV000020784 | pathogenic | Phenylketonuria | 1991-06-01 | no assertion criteria provided | literature only | |
De |
RCV000078531 | SCV000119728 | not provided | not provided | no assertion provided | not provided | ||
Counsyl | RCV000000634 | SCV001132267 | pathogenic | Phenylketonuria | 2018-11-06 | no assertion criteria provided | clinical testing | |
Natera, |
RCV000000634 | SCV001453101 | pathogenic | Phenylketonuria | 2020-09-16 | no assertion criteria provided | clinical testing | |
Prevention |
RCV004739274 | SCV005360008 | pathogenic | PAH-related disorder | 2024-04-07 | no assertion criteria provided | clinical testing | The PAH c.829T>G variant is predicted to result in the amino acid substitution p.Tyr277Asp. This variant has been reported, in homozygous state or in combination with a second pathogenic PAH variant, as causative for moderate or classic phenylketonuria (Pey et al. 2003. PubMed ID: 12655546; Sarkissian et al. 2012. PubMed ID: 23430918; Couce et al. 2013. PubMed ID: 23500595; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653; Table S1, Aldámiz-Echevarría et al. 2015. PubMed ID: 25882749; Hillert et al. 2020. PubMed ID: 32668217). It has been reported that the p.Tyr277 amino acid is near the active site of the enzyme, and functional studies of the p.Tyr277Asp variant have shown that this amino acid change completely abrogates the activity of the PAH enzyme (Pey et al. 2003. PubMed ID: 12655546; Shi et al. 2012. PubMed ID: 21953985). This variant has been interpreted as pathogenic by multiple outside laboratories, as well as the ClinGen PAH Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/603/). This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. |