Submissions for variant NM_000277.3(PAH):c.745C>T (p.Leu249Phe)

gnomAD frequency: 0.00003  dbSNP: rs74503222

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	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 (ga)	RCV000089076	SCV000203182	pathogenic	not provided	2014-04-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000089076	SCV000239070	pathogenic	not provided	2022-05-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); BH4 responsiveness in patients with L249F is unclear (Rivera et al., 2011); This variant is associated with the following publications: (PMID: 7913581, 8875186, 25750018, 21871829, 8533759, 18394115, 1349566, 8659548, 25155776, 18798839, 24765287, 24368688, 30037505, 27620137, 32668217, 32778825, 33465300, 33375644)
Invitae	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, LabCorp	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, Revvity	RCV000153634	SCV003826562	pathogenic	Phenylketonuria	2022-12-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000153634	SCV004209578	pathogenic	Phenylketonuria	2023-09-19	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.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	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, Inc.	RCV000153634	SCV001453109	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing