Submissions for variant NM_000277.3(PAH):c.1241A>G (p.Tyr414Cys)

gnomAD frequency: 0.00025  dbSNP: rs5030860

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000150074	SCV000852130	pathogenic	Phenylketonuria	2018-07-27	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM5: c.1240T>C likely pathogenic in ClinVar; PP3: All computational evidence supports deleterious effect. REVEL=0.982; PS3: 50% activity, 50% immunoreactivity (PMID:2044609); PM3_VeryStrong: Patient #41 p.R408W / p.Y414C, Phe 744 @dx and two homozygous individuals. Total of 9 patients with this variant (PMID:22526846; PMID:17935162; PMID:9399896; PMID:21871829; PMID:26542770); PP4_Moderate: BH4 defect excluded in all patients (PMID:22526846). 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: (PM5, PP3, PS3, PM3_VeryStrong, PP4_Moderate).
Eurofins Ntd Llc (ga)	RCV000078508	SCV000110364	pathogenic	not provided	2018-02-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000078508	SCV000239094	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Associated with tetrahydrobiopterin (BH4) responsiveness (PMID: 17935162); This variant is associated with the following publications: (PMID: 25750018, 10479481, 23500595, 20981092, 12655546, 24296287, 26919687, 26822130, 27469133, 15557004, 27121329, 26666653, 29030855, 34405919, 34828281, 15459954, 19609714, 18538294, 22975760, 22995991, 23559577, 20063067, 19036622, 21953985, 21228398, 26542770, 8889590, 12501224, 25087612, 26701937, 26503515, 26803807, 2014036, 14741196, 22526846, 22112818, 12655553, 11385716, 9450897, 8929956, 29499199, 30609409, 21871829, 9399896, 8556304, 30648773, 25596310, 30747360, 31980526, 31589614, 32668217, 33101986, 2044609, 34426522, 33375644, 32778825, 33465300, 29288420, 37421234, 36046396, 36699461, 36537053, 37443404, 17935162)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000078508	SCV000601708	pathogenic	not provided	2021-03-19	criteria provided, single submitter	clinical testing	This variant has been associated with marked decrease of PAH activity and at least mild PKU and BH4 responsiveness (PMIDs: 20063067(2010), 25596310 (2015), 30648773 (2019), and BIOPKU (http://www.biopku.org/)). Therefore, the variant is classified as pathogenic.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000078508	SCV000610853	pathogenic	not provided	2017-03-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000150074	SCV000611230	pathogenic	Phenylketonuria	2022-04-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000150074	SCV000629182	pathogenic	Phenylketonuria	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 414 of the PAH protein (p.Tyr414Cys). This variant is present in population databases (rs5030860, gnomAD 0.07%). This missense change has been observed in individual(s) with mild phenylketonuria (PKU) and non-PKU hyperphenylalaninemia (HPA) (PMID: 8556304, 9399896, 12655544, 20063067, 23764561). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 593). 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 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: 10479481, 17935162, 18538294, 19036622). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000150074	SCV000696426	pathogenic	Phenylketonuria	2016-02-18	criteria provided, single submitter	clinical testing	Variant summary: The c.1241A>G variant affects a conserved nucleotide, resulting in amino acid change from Tyr to Cys. 5/5 in-silico tools predict damaging outcome for this variant. This variant is found in 60/121344 control chromosomes at a frequency of 0.0004945, which does not exceed maximal expected frequency of a pathogenic allele (0.0079057). This variant has been reported in numerous patients with PKU or HPA at homozygous or compound heterozygous state. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150074	SCV000712023	pathogenic	Phenylketonuria	2016-04-25	criteria provided, single submitter	clinical testing	The p.Tyr414Cys variant in PAH is a well-established pathogenic variant for PKU and has been reported in more than 25 individuals with PKU in a homozygous state or compound heterozygous state with another pathogenic variant (Okano 1991, Nie lsen 2010, Couce 2013). This variant led to reduced enzyme activity in in vitro studies (Okano 1991, Benit 1999, Zurfluh 2008). The p.Tyr414Cys variant has been identified in 0.05% (60/121,344) of chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs5030860) though this frequen cy is low enough to be consistent with a recessive carrier frequency. In summary , this variant meets our criteria to be classified as pathogenic for PKU in an a utosomal recessive manner based upon case observations and functional evidence.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000150074	SCV000744089	pathogenic	Phenylketonuria	2014-10-08	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000150074	SCV000782465	pathogenic	Phenylketonuria	2016-06-16	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000150074	SCV001193979	pathogenic	Phenylketonuria	2019-11-12	criteria provided, single submitter	clinical testing	NM_000277.1(PAH):c.1241A>G(Y414C) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency, and can be associated with any form of the disease. Sources cited for classification include the following: PMID 12655553, 22112818, 11385716, 22526846, 2014036, 23500595, 8889590, 12501224, 17935162, 18538294, 21953985 and 15557004. Classification of NM_000277.1(PAH):c.1241A>G(Y414C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000078508	SCV001247319	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	PAH: PM3:Very Strong, PM2, PP4, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000150074	SCV001367638	pathogenic	Phenylketonuria	2018-10-31	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM1,PM3,PP3,PP2.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000150074	SCV001440693	pathogenic	Phenylketonuria	2019-01-01	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous.
Revvity Omics, Revvity	RCV000150074	SCV002016487	pathogenic	Phenylketonuria	2022-06-08	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000150074	SCV002557074	pathogenic	Phenylketonuria	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with phenylketonuria (PKU; MIM#261600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (100 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or very highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Biopterin_H domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a well-reported variant and is commonly described as a mild PKU variant (ClinVar, PKU database, PMID: 30668579). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Site-directed mutagenesis studies have shown a reduction to 28-80% in PAH activity compared to wild-type (PMID: 30037505). In the BioPKU database, this variant is reported to result in 57% residual enzyme activity (BioPKU). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Human Genetics, University Hospital Muenster	RCV004584304	SCV002577904	pathogenic	See cases	2021-12-20	criteria provided, single submitter	clinical testing	ACMG categories: PS1,PM2,PM3,PP3,PP4,PP5
3billion, Medical Genetics	RCV000150074	SCV003841538	pathogenic	Phenylketonuria	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.035%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 2014036, 2044609). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000593). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 17935162, 21871829, 22526846, 26542770, 9399896). A different missense change at the same codon (p.Tyr414His) has been reported to be associated with PAH-related disorder (PMID: 32668217). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000150074	SCV003920309	pathogenic	Phenylketonuria	2021-03-30	criteria provided, single submitter	clinical testing	PAH:NM_000277.1:exon12:c.1241A>G:p.Tyr414Cys Sequence analysis reveals a heterozygous c.1241A>G (p.Tyr414Cys) variant in the PAH gene. This variant is observed in 99/277184 allelles in the gnomAD database. In silico predictions by multiple algorithms indicate that this variant is deleterious on the function of the protein. Multiple entries in the Clinvar database classified this variant as pathogenic. Therefore this variant is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003398401	SCV004103364	pathogenic	PAH-related disorder	2023-10-04	criteria provided, single submitter	clinical testing	The PAH c.1241A>G variant is predicted to result in the amino acid substitution p.Tyr414Cys. This variant has been well documented to be causative for phenylalanine hydroxylase deficiency (Okano et al. 1991. PubMed ID: 2014036; Réblová et al. 2013. PubMed ID: 23357515). The p.Tyr414Cys substitution has been reported to reduce the activity of the PAH protein, with greatly varied estimates of residual activity ranging from ~10-80% of wild-type (Jennings et al. 2000. PubMed ID: 10980574; Couce et al. 2013. PubMed ID: 23500595; Danecka et al. 2015. PubMed ID: 25596310). The p.Tyr414Cys substitution has been reported to lead to a PAH protein that is responsive to BH4 (Zurflüh et al. 2008. PubMed ID: 17935162). This variant has been classified as pathogenic by the ClinGen PAH Variant Curation Expert Panel and many other laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/593/). Nearly forty patients homozygous for the c.1241A>G (p.Tyr414Cys) variant have been reported in the BioPKU database; all of these patients presented with either mild hyperphenylalaninemia (MHPA) or mild phenylketonuria (PKU) (http://www.biopku.org). Based on these observations, we classify the c.1241A>G (p.Tyr414Cys) variant as pathogenic.
Baylor Genetics	RCV000150074	SCV004201338	pathogenic	Phenylketonuria	2024-03-26	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000150074	SCV005043993	pathogenic	Phenylketonuria	2024-01-02	criteria provided, single submitter	clinical testing	PM5, PP3, PP4_Moderate, PS3_Very Strong
Daryl Scott Lab, Baylor College of Medicine	RCV003398401	SCV005871154	pathogenic	PAH-related disorder	2024-01-01	criteria provided, single submitter	clinical testing	PM5, PP3, PS3, PM3_VeryStrong, PP4_Moderate
OMIM	RCV000000624	SCV000020774	pathogenic	Hyperphenylalaninemia	2008-07-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000078508	SCV000119404	not provided	not provided		no assertion provided	not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000150074	SCV000733121	pathogenic	Phenylketonuria		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000150074	SCV001458996	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078508	SCV001954956	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000078508	SCV001966342	pathogenic	not provided		no assertion criteria provided	clinical testing