Submissions for variant NM_000277.3(PAH):c.805A>C (p.Ile269Leu)

dbSNP: rs62508692

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000281383	SCV000886598	pathogenic	Phenylketonuria	2018-12-10	reviewed by expert panel	curation	The c.805A>C (p.Ile269Leu) variant in PAH has been reported in multiple individuals with PAH deficiency, including non-PKU HPA (BH4 deficiency excluded). (PP4_Moderate; PMID10767174, PMID 2350059). This variant has an extremely low allele frequency in ExAC and gnomAD (PM2; ENF=0.00013). This variant was detected in trans with multiple known pathogenic variants: PMID 9521426: c.842+3G>C; PMID 10767174: R261X; PMID 14726806: E280K; PMID 21871829: IVS10-11G>A (PM3_Very-strong). Computational prediction tools and conservation analysis suggest this 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: PM3_Very-strong, PP4_Moderate, PM2, PP3.
Eurofins Ntd Llc (ga)	RCV000089101	SCV000330984	pathogenic	not provided	2015-06-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000281383	SCV000827700	pathogenic	Phenylketonuria	2024-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 269 of the PAH protein (p.Ile269Leu). This variant is present in population databases (rs62508692, gnomAD 0.02%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 9521426, 14726806, 21871829, 23500595). ClinVar contains an entry for this variant (Variation ID: 102842). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000281383	SCV000915570	likely pathogenic	Phenylketonuria	2018-11-02	criteria provided, single submitter	clinical testing	The PAH c.805A>C (p.Ile269Leu) variant has been reported in three studies in which it is found in a total of five individuals, including one sibling pair, with non-phenylketonuria hyperphenylalaninemia (non-PKU HPA). The variant was found in four individuals in a compound heterozygous state and in one individual in cis with a second missense variant and in trans with a third missense variant (Bosco et al. 1998; Rivera et al. 2011; Reblova et al. 2013). Control data are unavailable for the p.Ile269Leu variant which is reported at a frequency of 0.000464 in the Other population of the Genome Aggregation Database. Leandro et al. (2001) showed that the p.Ile269Leu variant caused a moderate reduction in the specific activity of the PAH enzyme as compared to wild type, when expressed in a prokaryotic expression system. Based on the evidence, the p.Ile269Leu variant is classified as likely pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000281383	SCV001362291	pathogenic	Phenylketonuria	2020-07-20	criteria provided, single submitter	clinical testing	Variant summary: PAH c.805A>C (p.Ile269Leu) results in a conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 251364 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (9.2e-05 vs 0.0079), allowing no conclusion about variant significance. c.805A>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency, including non-PKU hyperphenylalaninemia (e.g. Matalon_2004, Rivera_2011, Couce_2013, Reblova_2013). These data indicate that the variant is very likely to be associated with disease. In vitro studies demonstrated a moderate reduction in residual PAH activity (63%) as compared to wild type (Rivera_2011). Four ClinVar submitters including an expert panel (ClinGen PAH Variant Curation Expert Panel) (evaluation after 2014) cite the variant as pathogenic/likely pathogenic while, one ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000089101	SCV001784251	likely pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	Classified as responsive to tetrahydrobiopterin (BH4) therapy (PMID: 17935162); This variant is associated with the following publications: (PMID: 17924342, 10767174, 23357515, 34405919, 9521426, 17513426, 21871829, 23500595, 11708866, 14726806, 27121329, 32668217, 17935162, 9634518)
Revvity Omics, Revvity	RCV000281383	SCV002016489	pathogenic	Phenylketonuria	2021-11-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000281383	SCV002060316	likely pathogenic	Phenylketonuria	2021-11-01	criteria provided, single submitter	clinical testing	NM_000277.1(PAH):c.805A>C(I269L) is a missense variant classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency. Please note that the I269L variant can be associated with variant or non-PKU hyperphenylalaninemia. I269L has been observed in cases with relevant disease (PMID: 9521426, 14726806, 21871829, 23357515, 23942198, 24350308, 27121329). Functional assessments of this variant are available in the literature (Leandro_2001_(no PMID; article)). I269L has been observed in population frequency databases (gnomAD: AMR 0.02%). In summary, NM_000277.1(PAH):c.805A>C(I269L) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000281383	SCV002512203	pathogenic	Phenylketonuria	2022-01-07	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 strong, PM2 moderate, PM3 very strong, PP3 supporting, PP4 moderate
Fulgent Genetics, Fulgent Genetics	RCV000281383	SCV002811078	pathogenic	Phenylketonuria	2021-12-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000281383	SCV004201354	likely pathogenic	Phenylketonuria	2024-03-25	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089101	SCV000119708	not provided	not provided		no assertion provided	not provided
Elsea Laboratory, Baylor College of Medicine	RCV000281383	SCV001424211	likely pathogenic	Phenylketonuria	2020-04-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000281383	SCV001453104	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing