rs5030853
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 15P and 1B. PM1PM2PM5PP3PP5_Very_StrongBP4
The NM_000277.3(PAH):c.898G>T(p.Ala300Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,613,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A300V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.898G>T | p.Ala300Ser | missense_variant | 8/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.898G>T | p.Ala300Ser | missense_variant | 9/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.898G>T | p.Ala300Ser | missense_variant | 8/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000322 AC: 49AN: 152120Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000586 AC: 147AN: 251020Hom.: 0 AF XY: 0.000678 AC XY: 92AN XY: 135662
GnomAD4 exome AF: 0.000403 AC: 589AN: 1461672Hom.: 0 Cov.: 30 AF XY: 0.000468 AC XY: 340AN XY: 727150
GnomAD4 genome ? AF: 0.000322 AC: 49AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25AN XY: 74304
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:19Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Apr 01, 2023 | - - |
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 30, 2022 | The p.Ala300Ser variant in PAH is a well-established pathogenic variant in patients with phenylketonuria (Trefz 2009 PMID: 18956252, Heintz 2013 PMID: 23559577, Danecka 2015 PMID: 25596310), and is frequently associated with milder course and responsiveness to BH4 (Trefz 2009 PMID: 18956252, Heintz 2013 PMID: 23559577). In vitro functional studies provide some evidence that the p.Ala300Ser variant impacts protein function (Shen 2016 PMID: 26803807). This variant has been identified in 0.6% (67/10130) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs5030853). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis suggest that the p.Ala300Ser variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for phenylalanine hydroxylase deficiency in an autosomal recessive manner. ACMG/AMP Criteria applied PS3; PS4; PP3. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Mar 12, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 26, 2019 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | Sep 22, 2022 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Aug 10, 2018 | 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). - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Aug 06, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 13, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | 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. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Intergen, Intergen Genetics and Rare Diseases Diagnosis Center | Aug 29, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jan 19, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 30, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jul 30, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM5,PP2,PP3,PP5. - |
not provided Pathogenic:7Other:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | PAH: PS3:Very Strong, PM5, PP4:Moderate, PP3 - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 04, 2016 | - - |
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 16, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 23, 2020 | 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) - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 09, 2022 | 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. - |
Hyperphenylalaninemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 09, 2016 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at