Submissions for variant NM_000277.3(PAH):c.898G>T (p.Ala300Ser)

gnomAD frequency: 0.00034  dbSNP: rs5030853

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000150084	SCV000852126	pathogenic	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PP3: Deleterious in SIFT, Polyphen2, MutationTaster; PP4_Moderate: A300S found on 56/588 hyperphenylalaninemic patients, BH4 deficiency excluded. Upgraded per ClinGen Metabolic WG. (PMID:21147011); PM3_VeryStrong: Detected with c.1066-11G>A (P), R261Q(P/LP), L48S (P), R176X (P) in 20 patients. (PMID:21147011); PS3: A300S in vitro PAH activity of 31% (PMID:17935162). 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, PP4_Moderate, PM3_VeryStrong, PS3).
Eurofins Ntd Llc (ga)	RCV000078536	SCV000110392	pathogenic	not provided	2017-06-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000078536	SCV000239078	pathogenic	not provided	2020-07-23	criteria provided, single submitter	clinical testing	Typically associated with either mild hyperphenylalaninemia or mild PKU (Eiken et al., 1996; Danecka et al., 2015; Jeannesson-Thivisol et al., 2015); Published functional studies demonstrate A300S is associated with reduced residual phenylalanine hydroxylase enzyme activity compared to wild-type (Zurfluh et al. 2008; Danecka et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23500595, 26803807, 27682710, 30963030, 18538294, 30667134, 30487145, 25087612, 11486900, 24082139, 17935162, 1301187, 25596310, 23559577, 25750018, 25155776, 27469133, 27121329, 26666653, 28676969, 29431110, 29102225, 30037505, 31355225, 31589614, 33101986)
Illumina Laboratory Services, Illumina	RCV000150084	SCV000375565	pathogenic	Phenylketonuria	2016-06-14	criteria provided, single submitter	clinical testing	The c.898G>A (p.Ala300Ser) variant is well-documented in the literature and is associated with mild phenylketonuria phenotype that is responsive to BH4 treatment. Across a selection of available literature, the p.Ala300Ser variant has been identified in a homozygous state in at least two patients, in a compound heterozygous state in at least 20 patients, and in 40 patients whose zygosity was not explicitly stated but are presumed to be compound heterozygous (Eisensmith et al. 1992; Spaapen et al. 2001; Blau and Erlandsen 2004; Zurflüh et al. 2008; Bercovich et al. 2008; Couce et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00072 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Functional studies showed that the p.Ala300Ser variant did not affect enzyme activity, but resulted in severe misfolding and destabilization of the PAH protein (Gersting et al. 2008). Based on the collective evidence, the p.Ala300Ser variant is classified as pathogenic for phenylalanine hydroxylase deficiency.
Fulgent Genetics, Fulgent Genetics	RCV000150084	SCV000611236	pathogenic	Phenylketonuria	2022-05-30	criteria provided, single submitter	clinical testing
Invitae	RCV000150084	SCV000629225	pathogenic	Phenylketonuria	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 300 of the PAH protein (p.Ala300Ser). This variant is present in population databases (rs5030853, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with PAH deficiency-related diseases (PMID: 22330942, 23764561, 25155776, 25596310, 27682710). ClinVar contains an entry for this variant (Variation ID: 92751). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 15557004, 17935162, 18538294, 25596310, 26803807). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590551	SCV000696470	pathogenic	Hyperphenylalaninemia	2016-06-09	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.898G>T (p.Ala300Ser) variant involves the alteration of a conserved nucleotide within the catalytic domain. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 54/121010 control chromosomes at a frequency of 0.0004462, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant has been reported as one of the most common pathogenic variants that associate with a milder phenotype, which is consistant with the finding that p.Ala300Ser retains 31% of enzyme activity (Zurfluh_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000078536	SCV000889565	pathogenic	not provided	2016-10-04	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150084	SCV000967677	pathogenic	Phenylketonuria	2018-07-17	criteria provided, single submitter	clinical testing	The p.Ala300Ser variant in PAH is a well-established pathogenic variant in patie nts with phenylketonuria (Trefz 2009, Heintz 2013, Danecka 2015), and is frequen tly associated with milder course and responsiveness to BH4 (Trefz 2009, Heintz 2013). In vitro functional studies provide some evidence that the p.Ala300Ser va riant impacts protein function (Shen 2016). This variant has been identified in 0.6% (67/10130) of Ashkenazi Jewish chromosomes by the Genome Aggregation Databa se (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs5030853). Although this va riant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools a nd conservation analysis suggest that the p.Ala300Ser variant may impact the pro tein, though this information is not predictive enough to determine pathogenicit y. In summary, this variant meets criteria to be classified as pathogenic for ph enylketonuria in an autosomal recessive manner. ACMG/AMP Criteria applied PS3; P S4; PP3
Baylor Genetics	RCV000150084	SCV001163717	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000150084	SCV001194112	pathogenic	Phenylketonuria	2019-12-26	criteria provided, single submitter	clinical testing	NM_000277.1(PAH):c.898G>T(A300S) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and may be associated with classic, variant, or non-PKU hyperphenylalaninemia. Sources cited for classification include the following: PMID 9298832, 18538294, 23500595, 18299955, 16198137, 21147011, 15557004, 23792259, 24350308, and 17935162. Classification of NM_000277.1(PAH):c.898G>T(A300S) 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	RCV000078536	SCV001249175	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	PAH: PS3:Very Strong, PM5, PP4:Moderate, PP3
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000150084	SCV001251825	pathogenic	Phenylketonuria	2020-05-03	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000150084	SCV001368400	pathogenic	Phenylketonuria	2019-07-30	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM5,PP2,PP3,PP5.
Ambry Genetics	RCV001267463	SCV001445644	pathogenic	Inborn genetic diseases	2022-05-09	criteria provided, single submitter	clinical testing	The c.898G>T (p.A300S) alteration is located in coding exon 8 of the PAH gene. This alteration results from a G to T substitution at nucleotide position 898, causing the alanine (A) at amino acid position 300 to be replaced by a serine (S). Based on data from gnomAD, the T allele has an overall frequency of 0.05% (152/282410) total alleles studied. The highest observed frequency was 0.69% (71/10350) of Ashkenazi Jewish alleles. This alteration has been reported in individuals both homozygous and compound heterozygous with a second disease-causing allele and is typically associated with mild PKU or hyperphenylalaninemia (Bercovich, 2008; Dobrowolski, 2011; Couce, 2013; Réblová, 2013; Trunzo, 2013; Danecka, 2015; Jeannesson-Thivisol, 2015). Multiple studies have found that patients with this alteration are BH4-responsive (Zurflüh, 2008; Jeannesson-Thivisol, 2015; Shen, 2016). This amino acid position is highly conserved in available vertebrate species. The p.A300 amino acid is located in the catalytic domain of the protein. The serine substitution is too large for the side chain and destabilization is due to the change of polarity of the catalytic domain's core (reviewed in Blau, 2004). Functional analysis demonstrated the p.A300S alteration reduces protein activity to approximately 30% of wild type activity (Zurflüh, 2008; Shen, 2016). When co-expressed with other disease-causing alleles, residual activity has been reported from 5.2-18% of normal (Danecka, 2015; Shen, 2016). It has been determined that this alteration actually leads to conformational destabilization of the protein and increased degradation while the enzyme function remains intact (Gersting, 2008). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV000078536	SCV001755232	pathogenic	not provided	2021-07-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000150084	SCV001810539	pathogenic	Phenylketonuria	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000150084	SCV002016470	pathogenic	Phenylketonuria	2023-04-13	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000150084	SCV002099014	pathogenic	Phenylketonuria	2021-03-12	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000150084	SCV002556614	pathogenic	Phenylketonuria	2021-08-06	criteria provided, single submitter	clinical testing
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV000150084	SCV002574820	pathogenic	Phenylketonuria	2022-09-22	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000150084	SCV002579859	pathogenic	Phenylketonuria	2022-01-19	criteria provided, single submitter	clinical testing
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV000150084	SCV004030450	pathogenic	Phenylketonuria	2023-08-29	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000150084	SCV004804767	pathogenic	Phenylketonuria	2024-03-17	criteria provided, single submitter	research
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000078536	SCV000119761	not provided	not provided		no assertion provided	not provided
GenomeConnect, ClinGen	RCV000150084	SCV000840271	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.	RCV000150084	SCV001463134	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000078536	SCV001740375	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000078536	SCV001927245	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000150084	SCV003927833	pathogenic	Phenylketonuria	2023-04-01	no assertion criteria provided	clinical testing