ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1241A>G (p.Tyr414Cys) (rs5030860)

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Total submissions: 17
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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).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078508 SCV000110364 pathogenic not provided 2018-02-10 criteria provided, single submitter clinical testing
GeneDx RCV000078508 SCV000239094 pathogenic not provided 2016-11-30 criteria provided, single submitter clinical testing The Y414C missense variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. The Y414C variant is considered a mild PAH variant as it is associated with a significant amount of residual phenylalanine hydroxylase enzyme activity and has been described in association with mild phenylketonuria (PKU) or mild hyperphenylalaninemia (HPA) (Okano et al., 1991; Pey et al., 2004).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078508 SCV000601708 pathogenic not provided 2017-02-04 criteria provided, single submitter clinical testing
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 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000150074 SCV000629182 pathogenic Phenylketonuria 2020-01-02 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 414 of the PAH protein (p.Tyr414Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs5030860, ExAC 0.08%). This variant is the most common mild phenylketonuria (PKU) mutation in Europe, being especially frequent in the Scandinavian population and has been found to be associated with a range of clinical phenotypes (PMID: 12655544, 20063067, 23764561). It has been found as homozygous in individuals affected with mild PKU and non-PKU hyperphenylalaninemia (HPA) (PMID: 8556304, 9399896, 23764561). ClinVar contains an entry for this variant (Variation ID: 593). Experimental studies have shown that this missense change causes a mild decrease of the PAH enzymatic activity (PMID: 10479481, 17935162, 18538294, 19036622). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America 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, Partners HealthCare 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,; 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 Genetic Testing Laboratories,Mayo Clinic RCV000150074 SCV000782465 pathogenic Phenylketonuria 2016-06-16 criteria provided, single submitter clinical testing
Myriad Women's Health, 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 Praxis fuer Humangenetik Tuebingen RCV000078508 SCV001247319 pathogenic not provided 2020-04-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197003 SCV001367638 pathogenic Cardiomyopathy; Global developmental delay; Waddling gait; Short stature; Choanal atresia; Microcephaly; Delayed cranial suture closure; Proximal muscle weakness in lower limbs; Small hand 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,PS3,PM4. This variant was detected in heterozygous state.
OMIM RCV000000624 SCV000020774 pathogenic Hyperphenylalaninemia, non-pku 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

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