ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1222C>T (p.Arg408Trp) (rs5030858)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000000607 SCV000852102 pathogenic Phenylketonuria 2018-08-06 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PP3: ; PS3: PMID 17935162: Table 1: p.Arg408Trp 1.85% WT activity PMID 25596310: 1.3% activity of WT (Table S4) (PMID:25596310; PMID:17935162); PP4_Moderate: most common PAH mutation in cohort; exclude BH4 deficiency. (PMID:25596310; PMID:9634518); PM3_Strong: Detected with IVS12+1G>A, M1V (Pathogenic/LP) (PMID:9634518; PMID:1971147; PMID:1609797). 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: (PP3, PS3, PP4_Moderate, PM3_Strong).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078507 SCV000110363 pathogenic not provided 2017-05-03 criteria provided, single submitter clinical testing
GeneDx RCV000078507 SCV000239093 pathogenic not provided 2017-03-24 criteria provided, single submitter clinical testing The R408W missense variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. The R408W variant is considered a severe PAH pathogenic variant. Patients homozygous for the R408W variant have classic PKU and functional analysis found that it is associated with significantly reduced enzyme activity (Guldberg et al., 1998; Okano et al., 1991). The R408W variant is classified as not responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh et al. 2008).
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000078507 SCV000280612 pathogenic not provided 2015-12-23 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000000607 SCV000375560 pathogenic Phenylketonuria 2017-04-27 criteria provided, single submitter clinical testing The PAH c.1222C>T (p.Arg408Trp) variant is a well-documented missense variant that has been identified in many patients with phenylalanine hydroxylase deficiency (DiLella et al. 1987; Zurflüh et al. 2008). Across a selection of the available literature, the p.Arg408Trp variant has been identified in a homozygous state in 24 patients and in a compound heterozygous state in at least 106 patients (Karacić et al. 2009; Utz et al. 2012; Sterl et al. 2013). Control data are not available from thse studies for this variant, which is reported at a frequency of 0.00174 in the European-American population of the Exome Sequencing Project. Functional studies in E coli with p.Arg408Trp-PAH or wild type PAH demonstrated that the p.Arg408Trp-PAH formed high molecular weight aggregates, suggesting a severe folding defect (Gersting et al. 2008). Based on the collective evidence, the p.Arg408Trp variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000000607 SCV000538052 pathogenic Phenylketonuria 2015-08-13 criteria provided, single submitter clinical testing The c.1222C>T (p. Arg408Trp) missense variant in the PAH gene has been shown to segregate with PKU in a family, wherein the affected individual was found to be homozygous [DiLella AG et al., (1987)]. This variant is predominantly found in the Eastern European population who were diagnosed with PKU [Zschocke J, (2003)]. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls [Zurflüh MR et al., (2008)]. Furthermore, protein-expression studies in E.coli, using human cDNA containing this variant, showed 100% protein aggregation, which suggests a severe folding defect and loss of function [Gersting SW et al., (2008)]. The frequency of this variant in the population databases (1000Genome, Exome Sequencing Project and ExAC) is lower than the disease-allele frequency and there are no homozygotes present. Several computational algorithms predict a deleterious effect of this variant on the protein. Finally, a reputable source has also classified this variant as Pathogenic. Therefore, the collective evidence supports a classification of the c.1222C>T (p. Arg408Trp) variant in the PAH gene as Pathogenic. We have confirmed this finding in our laboratory using Sanger sequencing.
Fulgent Genetics,Fulgent Genetics RCV000000607 SCV000611229 pathogenic Phenylketonuria 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000000607 SCV000629181 pathogenic Phenylketonuria 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 408 of the PAH protein (p.Arg408Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs5030858, ExAC 0.1%). This variant is the most prevalent and widely distributed PKU-causing allele in the European population (PMID: 2014036, 8097262, 12173030, 25596310, 23430547). ClinVar contains an entry for this variant (Variation ID: 577). Experimental studies have shown that this missense change results in reduced protein stability and accelerated degradation, and an enzyme lack of residual activity (PMID: 18538294, 17935162, 19036622, 12655546, 2014036, 21953985, 18937047). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000000607 SCV000696432 pathogenic Phenylketonuria 2016-12-07 criteria provided, single submitter clinical testing Variant summary: The c.1222C>T (p.Arg408Trp) in PAH gene is a missense change that involves a non-conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant of interest is located within the catalytic domain and mutations were proven to lead to severe aggregation and complete disruption of structural integrity, and, as a result, complete abolishment of all residual enzyme activity. The variant is present in the large control population dataset of ExAC at a frequency 0.00066 (80/121328 chrs tested), predominantly in individuals of European descent (0.0011; 74/66718) which does not exceed the maximal expected frequency of a pathogenic allele (0.0079) in this gene. The variant has been identified homozygously or in the compound heterozygous state in numerous affected individuals with severe presentation. It is listed as the most common missense pathogenic variant in European population. Lastly, multiple reputable databases/diagnostic centers classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000000607 SCV000744090 pathogenic Phenylketonuria 2014-10-08 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000000607 SCV000745569 pathogenic Phenylketonuria 2016-05-04 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000000607 SCV000803784 pathogenic Phenylketonuria 2017-08-16 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078507 SCV000889563 pathogenic not provided 2016-04-29 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000000607 SCV001194061 pathogenic Phenylketonuria 2019-10-18 criteria provided, single submitter clinical testing NM_000277.1(PAH):c.1222C>T(R408W) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and is associated with classic PKU. Sources cited for classification include the following: PMIDs: 17935162, 16879198, 22513348, 18538294, 1671768, 2884570, 8889590. Classification of NM_000277.1(PAH):c.1222C>T(R408W) 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 RCV000078507 SCV001247320 pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing
Human Genetics Institute Leipzig, Universitätsklinikum Leipzig RCV000000607 SCV001251403 pathogenic Phenylketonuria 2019-10-30 criteria provided, single submitter clinical testing
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000000607 SCV001251469 pathogenic Phenylketonuria criteria provided, single submitter research The PAH c.1222C>T (p.R408W) missense variant has been reported in multiple individuals with phenylketonuria and results in an amino acid change in the catalytic domain of the encoded protein (PMID: 7833927; 1312992; 8659548; 18538294).
OMIM RCV000000607 SCV000020757 pathogenic Phenylketonuria 2008-07-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078507 SCV000119395 not provided not provided no assertion provided not provided
GeneReviews RCV000000607 SCV000324891 pathogenic Phenylketonuria 2016-10-20 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000000607 SCV000840270 not provided Phenylketonuria no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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