Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000153634 | SCV000852151 | pathogenic | Phenylketonuria | 2018-08-12 | reviewed by expert panel | curation | PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. Extremely low frequency in ExAC and gnomAD (0.00004065); PP3: Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.981; PP4_Moderate: L249F was seen 3 times in HPA patients associated with 2 different haplotypes. DHPR defeciency was excluded. Upgraded per ClinGen Metabolic workgroup. (PMID:8533759); PM3_VeryStrong: Seen with R261X, A309V, V388M, R261Q. All Pathogenic/Likely Pathogenic in ClinVar. Upgraded per ClinGen SVI Workgroup (PMID:21871829; PMID:24765287). 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, PP3, PP4_Moderate, PM3_VeryStrong). |
Eurofins Ntd Llc |
RCV000089076 | SCV000203182 | pathogenic | not provided | 2014-04-30 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000089076 | SCV000239070 | pathogenic | not provided | 2024-10-17 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; BH4 responsiveness in patients with p.(L249F) is unclear (PMID: 21871829); This variant is associated with the following publications: (PMID: 7913581, 8875186, 25750018, 8533759, 18394115, 1349566, 8659548, 18798839, 24765287, 24368688, 30037505, 27620137, 33375644, 32778825, 37421234, 32668217, 21871829, 25155776, 33465300) |
Labcorp Genetics |
RCV000153634 | SCV000629213 | pathogenic | Phenylketonuria | 2024-01-24 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 249 of the PAH protein (p.Leu249Phe). This variant is present in population databases (rs74503222, gnomAD 0.01%). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 1349566, 8533759, 24368688, 24765287, 25155776; Invitae). ClinVar contains an entry for this variant (Variation ID: 102821). 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%. For these reasons, this variant has been classified as Pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000153634 | SCV000696465 | pathogenic | Phenylketonuria | 2017-05-26 | criteria provided, single submitter | clinical testing | Variant summary: The PAH c.745C>T (p.Leu249Phe) variant located in the Aromatic amino acid hydroxylase, C-terminal domain (via InterPro) involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a damaging outcome. This variant was found in 3/121308 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). Multiple publications have cited the variant in affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. |
Revvity Omics, |
RCV000153634 | SCV003826562 | pathogenic | Phenylketonuria | 2022-12-01 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV000153634 | SCV004209578 | pathogenic | Phenylketonuria | 2024-03-24 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000089076 | SCV004222247 | pathogenic | not provided | 2022-10-21 | criteria provided, single submitter | clinical testing | The frequency of this variant in the general population, 0.00014 (3/21632 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant is associated with a variable phenotype that ranges from non-PKU hyperphenylalaninemia to classic PKU (PMIDs: 25155776 (2014), 24368688 (2014), 23357515 (2013), 23430918 (2012), 22112818 (2012), 24765287 (2011), 21871829 (2011), 18798839 (2008), 18394115 (2008), 12173030 (2002), 11385716 (2001), 10429004 (1999), 9634518 (1998), 8831077 (1996), 8632937 (1996), 8533759 (1995), and 1349566 (1992)). In addition, this variant has been observed in individuals with reported PAH deficiency with undetermined PAH enzymatic activity (PMID: 21871829 (2011)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. |
De |
RCV000089076 | SCV000119682 | not provided | not provided | no assertion provided | not provided | ||
Counsyl | RCV000153634 | SCV000486191 | pathogenic | Phenylketonuria | 2016-05-27 | no assertion criteria provided | clinical testing | |
Natera, |
RCV000153634 | SCV001453109 | pathogenic | Phenylketonuria | 2020-09-16 | no assertion criteria provided | clinical testing |