ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.755G>A (p.Arg252Gln)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000277.3(PAH):c.755G>A (p.Arg252Gln)
Variation ID: 102824 Accession: VCV000102824.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q23.2 12: 102852902 (GRCh38) [ NCBI UCSC ] 12: 103246680 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 19, 2014 Feb 14, 2024 Aug 10, 2018 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000277.3:c.755G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000268.1:p.Arg252Gln missense NM_001354304.2:c.755G>A NP_001341233.1:p.Arg252Gln missense NC_000012.12:g.102852902C>T NC_000012.11:g.103246680C>T NG_008690.2:g.110509G>A P00439:p.Arg252Gln - Protein change
- R252Q
- Other names
- NM_000277.1(PAH):c.755G>A
- Canonical SPDI
- NC_000012.12:102852901:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PAH | - | - |
GRCh38 GRCh37 |
1485 | 1604 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 28, 2022 | RCV000089080.11 | |
Pathogenic (8) |
reviewed by expert panel
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Aug 10, 2018 | RCV000179742.19 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Aug 10, 2018)
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reviewed by expert panel
Method: curation
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Phenylketonuria
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen PAH Variant Curation Expert Panel
Accession: SCV000852163.4
First in ClinVar: Jun 28, 2015 Last updated: Dec 11, 2022 |
Comment:
PAH-specific ACMG/AMP criteria applied: PM2: ; PP3: tools predict damaging; PS3: BioPKU 3% enzyme activity; 3.8% residual activity (PMID:24401910); PM3: Detected in trans with p.Pro407fs … (more)
PAH-specific ACMG/AMP criteria applied: PM2: ; PP3: tools predict damaging; PS3: BioPKU 3% enzyme activity; 3.8% residual activity (PMID:24401910); PM3: Detected in trans with p.Pro407fs (PMID:7833954); PP4_Moderate: Detected in 2 patients with classic PKU (Phe>1.5mM). BH4 deficiency excluded (PMID:7833954; PMID:9634518). 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: (PM2, PP3, PS3, PM3, PP4_Moderate). (less)
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Likely pathogenic
(Mar 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003920888.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
PAH NM_000277.2 exon 7 p.Arg252Gln (c.755G>A): This variant has been reported in the literature as a compound heterozygote in at least 1 individual with PKU … (more)
PAH NM_000277.2 exon 7 p.Arg252Gln (c.755G>A): This variant has been reported in the literature as a compound heterozygote in at least 1 individual with PKU (Benit 1994 PMID:7833954) and has been reported in the BIOPKU database (http://www.biopku.org). This variant is present in 0.005% (1/19948) of East Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/12-103246680-C-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status and/or variable expressivity. This variant is present in ClinVar (Variation ID:102824). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, computational tools designed to predict splicing suggest a potential effect from this variant. However, further studies are needed to understand its impact. Functional studies support a deleterious effect of this variant, suggesting decreased protein production or activity compared to wild-type (Bjorgo 1998 PMID:9799096, Shi 2012 PMID:21953985, Himmelreich 2018 PMID:30037505). Furthermore, other variants at this same codon (p.Arg252Pro, p.Arg252Trp, p.Arg252Gly) have been reported in the literature, with at least one of these variants with sufficient evidence for association with disease. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic. (less)
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Pathogenic
(Nov 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000944724.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 252 of the PAH protein (p.Arg252Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 252 of the PAH protein (p.Arg252Gln). This variant is present in population databases (rs62644503, gnomAD 0.005%). This missense change has been observed in individuals with phenylketonuria (PMID: 7833954, 16256386, 23430547, 24401910, 30050108). ClinVar contains an entry for this variant (Variation ID: 102824). 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: 11243094, 17924342, 21953985). This variant disrupts the p.Arg252 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2574153, 8116675, 12655546, 17096675, 20082265, 25596310). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 28, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000232039.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 5
Sex: mixed
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893944.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Dec 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361334.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: PAH c.755G>A (p.Arg252Gln) results in a conservative amino acid change located in the aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded … (more)
Variant summary: PAH c.755G>A (p.Arg252Gln) results in a conservative amino acid change located in the aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251262 control chromosomes. c.755G>A has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Benit_1994, Liang_2014, Li_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in categorization as a functionally hemizygous variant with less than 10% of normal activity (Li_2018). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601717.2
First in ClinVar: Mar 19, 2014 Last updated: Jan 03, 2022 |
Comment:
The variant is associated with classic PKU in the published literature (PMID: 9634518 (1998), 24401910 (2014)). Assessment of experimental evidence regarding the effect of this … (more)
The variant is associated with classic PKU in the published literature (PMID: 9634518 (1998), 24401910 (2014)). Assessment of experimental evidence regarding the effect of this variant suggests it disrupts normal PAH enzymatic activity (PMID: 24401910 (2014), 21953985 (2012), 11243094 (1997)). Therefore, the variant is classified as pathogenic. (less)
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Pathogenic
(Sep 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002576977.2
First in ClinVar: Oct 08, 2022 Last updated: Mar 04, 2023 |
Comment:
Reported in an individual with PKU who harbored a second PAH variant (Benit et al., 1994); Functional analysis demonstrates decreased PAH enzyme activity (Liang et … (more)
Reported in an individual with PKU who harbored a second PAH variant (Benit et al., 1994); Functional analysis demonstrates decreased PAH enzyme activity (Liang et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 21228398, 30747360, 21953985, 7833954, 8188310, 24401910, 27264808, 9634518, 11243094, 30037505, 30275481, 34426522, 31589614, 32668217, 32778825) (less)
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Pathogenic
(Oct 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004201363.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002573148.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). It is located in a mutational hot … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24401910). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.99). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 7833954). Different missense changes at the same codon (p.Arg252Gly, p.Arg252Pro, p.Arg252Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000584 , VCV000102823 , VCV000932252). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Global developmental delay (present)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001453107.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE
Accession: SCV000119686.1
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Analysis of the genotype-phenotype correlation in patients with phenylketonuria in mainland China. | Li N | Scientific reports | 2018 | PMID: 30050108 |
Mapping the functional landscape of frequent phenylalanine hydroxylase (PAH) genotypes promotes personalised medicine in phenylketonuria. | Danecka MK | Journal of medical genetics | 2015 | PMID: 25596310 |
The mutation spectrum of the phenylalanine hydroxylase (PAH) gene and associated haplotypes reveal ethnic heterogeneity in the Taiwanese population. | Liang Y | Journal of human genetics | 2014 | PMID: 24401910 |
Molecular Genetics and Genotype-Based Estimation of BH4-Responsiveness in Serbian PKU Patients: Spotlight on Phenotypic Implications of p.L48S. | Djordjevic M | JIMD reports | 2013 | PMID: 23430547 |
Protein stability and in vivo concentration of missense mutations in phenylalanine hydroxylase. | Shi Z | Proteins | 2012 | PMID: 21953985 |
Variations in genotype-phenotype correlations in phenylketonuria patients. | Santos LL | Genetics and molecular research : GMR | 2010 | PMID: 20082265 |
Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases. | Pey AL | American journal of human genetics | 2007 | PMID: 17924342 |
Molecular epidemiology of phenylalanine hydroxylase deficiency in Southern Italy: a 96% detection rate with ten novel mutations. | Daniele A | Annals of human genetics | 2007 | PMID: 17096675 |
Phenylketonuria mutations in Northern China. | Song F | Molecular genetics and metabolism | 2005 | PMID: 16256386 |
Phenylketonuria: genotype-phenotype correlations based on expression analysis of structural and functional mutations in PAH. | Pey AL | Human mutation | 2003 | PMID: 12655546 |
A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype. | Guldberg P | American journal of human genetics | 1998 | PMID: 9634518 |
Two novel mutations in phenylalanine hydroxylase gene and in vitro expression analysis on mutation Arg252Gln. | Zhang M | Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih | 1997 | PMID: 11243094 |
Gypsy phenylketonuria: a point mutation of the phenylalanine hydroxylase gene in Gypsy families from Slovakia. | Kalanin J | American journal of medical genetics | 1994 | PMID: 8116675 |
Novel frame shift deletions of the phenylalanine hydroxylase gene in phenylketonuria. | Bénit P | Human molecular genetics | 1994 | PMID: 8069318 |
Five novel missense mutations of the phenylalanine hydroxylase gene in phenylketonuria. | Bénit P | Human mutation | 1994 | PMID: 7833954 |
CpG dinucleotides are mutation hot spots in phenylketonuria. | Abadie V | Genomics | 1989 | PMID: 2574153 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ab854b7c-19a6-4553-ac95-af437437cddf | - | - | - | - |
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Text-mined citations for rs62644503 ...
HelpRecord last updated Feb 14, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.