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

gnomAD frequency: 0.00092  dbSNP: rs5030858

Total submissions: 36

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).
Eurofins Ntd Llc (ga)	RCV000078507	SCV000110363	pathogenic	not provided	2017-05-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000078507	SCV000239093	pathogenic	not provided	2019-11-14	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Classified as not responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh et al., 2008); This variant is associated with the following publications: (PMID: 2014036, 9634518, 25596310, 17935162, 1677425, 32853555, 8188310, 33101986, 31589614, 30747360, 31355225, 1355066, 30963030, 30667134, 8825928, 29030855, 30037505, 1609797, 1971147, 29499199, 19194782, 16338627, 29102225, 24741310, 27786189, 22513348, 23792259, 12501224, 9452062, 8889590, 26803807, 2884570, 12542580, 26919687, 26542770, 24939588, 26210745, 25750018, 20981092, 22975760, 25087612, 24401910, 18538294, 12655546, 23500595, 23559577, 21953985, 18937047, 19036622)
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 Laboratory Services, 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	2022-05-11	criteria provided, single submitter	clinical testing
Invitae	RCV000000607	SCV000629181	pathogenic	Phenylketonuria	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 408 of the PAH protein (p.Arg408Trp). This variant is present in population databases (rs5030858, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with phenylketonuria (PKU) and is the most prevalent and widely distributed PKU-causing allele in the European population (PMID: 2014036, 8097262, 12173030, 23430547, 25596310). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 577). 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%. Experimental studies have shown that this missense change affects PAH function (PMID: 2014036, 12655546, 17935162, 18538294, 18937047, 19036622, 21953985). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, 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	2021-03-19	criteria provided, single submitter	clinical testing	The PAH c.1222C>T (p.Arg408Trp) variant has been associated with null to very low PAH activity and classical PKU (PMIDs: 18937047 (2009), 23500595 (2013), 30037505 (2018), 30747360 (2019), and 31355225 (2019)). Therefore, the variant is classified as pathogenic.
Myriad Genetics, 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 Center for Human Genetics Tuebingen	RCV000078507	SCV001247320	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	PAH: PM3:Very Strong, PS3, PP4:Moderate, PM2:Supporting
Institute of Human Genetics, University of Leipzig Medical Center	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).
Revvity Omics, Revvity	RCV000000607	SCV002016472	pathogenic	Phenylketonuria	2023-12-28	criteria provided, single submitter	clinical testing
3billion	RCV000000607	SCV002058424	pathogenic	Phenylketonuria	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000577, PMID:2884570, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 25596310, 17935162, PS3_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 1609797, 9634518, 1971147, PM3_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000612, PMID:28540274,1312992, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.887, 3CNET: 0.996, PP3_P). A missense variant is a common mechanism associated with Phenylketonuria; PKU (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000891, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Centogene AG - the Rare Disease Company	RCV000000607	SCV002059749	pathogenic	Phenylketonuria	2019-09-06	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV002287314	SCV002577905	pathogenic	Reduced phenylalanine hydroxylase level	2021-12-20	criteria provided, single submitter	clinical testing	ACMG categories: PS1,PM2,PM7,PP3,PP4,PP5,BP1
MGZ Medical Genetics Center	RCV000000607	SCV002581517	pathogenic	Phenylketonuria	2022-07-19	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000000607	SCV002761510	pathogenic	Phenylketonuria	2022-01-13	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000000607	SCV002768917	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. 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 arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (252 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (14 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated catalytic domain (PMID: 30037505). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is one of the most common variants reported in individuals with classic PKU (ClinVar, PMIDs: 26481238, 25596310, 30037505, 30668579). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Site-directed mutagenesis studies have shown a reduction to 2% in PAH activity compared to wild-type (PMID: 30037505). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV002512607	SCV003529633	pathogenic	Inborn genetic diseases	2021-07-08	criteria provided, single submitter	clinical testing	The c.1222C>T (p.R408W) alteration is located in exon 12 (coding exon 12) of the PAH gene. This alteration results from a C to T substitution at nucleotide position 1222, causing the arginine (R) at amino acid position 408 to be replaced by a tryptophan (W). This common mutation has been reported in multiple homozygous and compound heterozygous individuals with phenylalanine hydroxylase (PAH) deficiency (DiLella, 1987; Guldberg, 1995; Guldberg, 1998; Gundorova, 2019; Lillev&auml;li, 2019; Su, 2019; Tresbach, 2020). This alteration is located in the catalytic domain at the center of the protein structure and leads to severe aggregation with complete disruption of structural integrity and loss of enzyme function (Dobrowolski, 2009; Gersting, 2008). The p.R408W alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003415607	SCV004115100	pathogenic	PAH-related condition	2023-06-01	criteria provided, single submitter	clinical testing	The PAH c.1222C>T variant is predicted to result in the amino acid substitution p.Arg408Trp. This variant is one of the most commonly reported pathogenic PAH variants and has been associated with classical phenylketonuria (PKU) (DiLella et al. 1987. PubMed ID: 2884570; Guldberg et al. 1994. PubMed ID: 8088845; Danecka et al. 2015. PubMed ID: 25596310). The p.Arg408Trp amino acid change has been reported to reduce the activity of the PAH protein to <2% of wild-type, and is reported to result in a PAH protein that is non-responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). Over 1800 patients homozygous for this variant have been reported in the BioPKU database; over 99% of the reported patients presented with classic PKU (http://www.biopku.org). The c.1222C>T variant is interpreted as pathogenic by the ClinGen PAH Variant Curation Expert Panel and other outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/577/). We also interpret this variant as pathogenic.
Baylor Genetics	RCV000000607	SCV004201317	pathogenic	Phenylketonuria	2023-10-30	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000078507	SCV004226631	pathogenic	not provided	2023-06-19	criteria provided, single submitter	clinical testing	PP3, PP4_moderate, PM3_strong, PS3
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000000607	SCV004244666	pathogenic	Phenylketonuria	2023-10-30	criteria provided, single submitter	clinical testing	PS3, PM3_Strong, PM5, PP3
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	not provided	Phenylketonuria		no assertion 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.
Natera, Inc.	RCV000000607	SCV001463113	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078507	SCV001952974	pathogenic	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000000607	SCV004099402	pathogenic	Phenylketonuria	2023-10-30	no assertion criteria provided	clinical testing