The c.890G>A (p.Arg297His) variant in PAH has been reported in 6 patients with PKU, in trans with established pathogenic variants (PMID: 9298832,24401910) with BH4 deficiency excluded in one (PMIDs 24401910 & 9298832). This variant has an extremely low allele frequency in gnomAD (2/245792). The arginine at position 297 is in the C-terminal aromatic amino acid hydroxylase domain, and computational prediction tools and conservation analysis suggest that the c.890G>A variant may impact the protein function. Mutant enzyme activity is 20% as compared to wild type (PMID:24401910). Overall, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PP4_moderate, PM2, PM3_strong, PS3.
ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.890G>A (p.Arg297His)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
for
Phenylketonuria
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000277.3(PAH):c.890G>A (p.Arg297His)
Variation ID: 92750 Accession: VCV000092750.42
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q23.2 12: 102851709 (GRCh38) [ NCBI UCSC ] 12: 103245487 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 20, 2024 Jul 7, 2019 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000277.3:c.890G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000268.1:p.Arg297His missense NM_001354304.2:c.890G>A NP_001341233.1:p.Arg297His missense NC_000012.12:g.102851709C>T NC_000012.11:g.103245487C>T NG_008690.2:g.111702G>A P00439:p.Arg297His - Protein change
- R297H
- Other names
- -
- Canonical SPDI
- NC_000012.12:102851708:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00000
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| LOC126861615 | - | - | - | GRCh38 | - | 84 |
| PAH | - | - |
GRCh38 GRCh37 |
1506 | 1629 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2020 | RCV000078535.34 | |
| Pathogenic (8) |
reviewed by expert panel
|
Jul 7, 2019 | RCV000150085.29 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 11, 2017 | RCV000588535.9 |
Submissions - Germline
| Classification
Help
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
Help
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jul 07, 2019)
|
reviewed by expert panel
Method: curation
|
Phenylketonuria
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen PAH Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV001146750.1 First in ClinVar: Jan 20, 2020 Last updated: Jan 20, 2020 |
Comment:
The c.890G>A (p.Arg297His) variant in PAH has been reported in 6 patients with PKU, in trans with established pathogenic variants (PMID: 9298832,24401910) with BH4 deficiency … (more)
The c.890G>A (p.Arg297His) variant in PAH has been reported in 6 patients with PKU, in trans with established pathogenic variants (PMID: 9298832,24401910) with BH4 deficiency excluded in one (PMIDs 24401910 & 9298832). This variant has an extremely low allele frequency in gnomAD (2/245792). The arginine at position 297 is in the C-terminal aromatic amino acid hydroxylase domain, and computational prediction tools and conservation analysis suggest that the c.890G>A variant may impact the protein function. Mutant enzyme activity is 20% as compared to wild type (PMID:24401910). Overall, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PP4_moderate, PM2, PM3_strong, PS3. (less)
|
|
|
Pathogenic
(Aug 11, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperphenylalaninemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696469.1
First in ClinVar: Mar 20, 2018 Last updated: Mar 20, 2018 |
Comment:
Variant summary: The PAH c.890G>A (p.Arg297His) variant located in the aromatic amino acid hydroxylase, C-terminal domain (via InterPro) involves the alteration of a conserved nucleotide … (more)
Variant summary: The PAH c.890G>A (p.Arg297His) variant located in the aromatic amino acid hydroxylase, C-terminal domain (via InterPro) involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a damaging outcome. A functional study, Liang_2014, supports these predictions finding the variant to significantly decreased PAH activity. This variant was found in 1/121030 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). Multiple publications have cited the variant in affected individuals with mild forms of hyperphenylalaninemia. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Dec 21, 2012)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000110391.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Jan 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004209665.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(May 20, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV005200806.1
First in ClinVar: Sep 08, 2024 Last updated: Sep 08, 2024 |
Comment:
PP3, PP4_moderate, PM2, PM3_strong, PS3
|
|
|
Pathogenic
(Feb 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001334784.25
First in ClinVar: Jun 08, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893940.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Nov 17, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000485321.2
First in ClinVar: Jun 28, 2015 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Dec 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001206964.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 297 of the PAH protein (p.Arg297His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 297 of the PAH protein (p.Arg297His). This variant is present in population databases (rs62642939, gnomAD 0.006%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 9298832, 16198137, 23430547, 24401910, 25596310). ClinVar contains an entry for this variant (Variation ID: 92750). 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: 24401910, 30037505). This variant disrupts the p.Arg297 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8807331, 10234516, 21307867, 23357515, 27121329). 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)
|
|
|
Pathogenic
(Mar 17, 2024)
|
criteria provided, single submitter
Method: research
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804990.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001463136.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE
Accession: SCV000119758.1
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
Variant summary: The PAH c.890G>A (p.Arg297His) variant located in the aromatic amino acid hydroxylase, C-terminal domain (via InterPro) involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a damaging outcome. A functional study, Liang_2014, supports these predictions finding the variant to significantly decreased PAH activity. This variant was found in 1/121030 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). Multiple publications have cited the variant in affected individuals with mild forms of hyperphenylalaninemia. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
PP3, PP4_moderate, PM2, PM3_strong, PS3
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 297 of the PAH protein (p.Arg297His). This variant is present in population databases (rs62642939, gnomAD 0.006%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 9298832, 16198137, 23430547, 24401910, 25596310). ClinVar contains an entry for this variant (Variation ID: 92750). 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: 24401910, 30037505). This variant disrupts the p.Arg297 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8807331, 10234516, 21307867, 23357515, 27121329). 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.
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. |
Comment:
The c.890G>A (p.Arg297His) variant in PAH has been reported in 6 patients with PKU, in trans with established pathogenic variants (PMID: 9298832,24401910) with BH4 deficiency excluded in one (PMIDs 24401910 & 9298832). This variant has an extremely low allele frequency in gnomAD (2/245792). The arginine at position 297 is in the C-terminal aromatic amino acid hydroxylase domain, and computational prediction tools and conservation analysis suggest that the c.890G>A variant may impact the protein function. Mutant enzyme activity is 20% as compared to wild type (PMID:24401910). Overall, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PP4_moderate, PM2, PM3_strong, PS3.
Comment:
Variant summary: The PAH c.890G>A (p.Arg297His) variant located in the aromatic amino acid hydroxylase, C-terminal domain (via InterPro) involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a damaging outcome. A functional study, Liang_2014, supports these predictions finding the variant to significantly decreased PAH activity. This variant was found in 1/121030 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). Multiple publications have cited the variant in affected individuals with mild forms of hyperphenylalaninemia. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
PP3, PP4_moderate, PM2, PM3_strong, PS3
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 297 of the PAH protein (p.Arg297His). This variant is present in population databases (rs62642939, gnomAD 0.006%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 9298832, 16198137, 23430547, 24401910, 25596310). ClinVar contains an entry for this variant (Variation ID: 92750). 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: 24401910, 30037505). This variant disrupts the p.Arg297 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8807331, 10234516, 21307867, 23357515, 27121329). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Relationship between genotype, phenylalanine hydroxylase expression and in vitro activity and metabolic phenotype in phenylketonuria. | Himmelreich N | Molecular genetics and metabolism | 2018 | PMID: 30037505 |
| Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria. | Aldámiz-Echevarría L | Journal of human genetics | 2016 | PMID: 27121329 |
| 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 of PKU in Poland and potential impact of mutations on BH4 responsiveness. | Bik-Multanowski M | Acta biochimica Polonica | 2013 | PMID: 24350308 |
| 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 |
| Hyperphenylalaninemia in the Czech Republic: genotype-phenotype correlations and in silico analysis of novel missense mutations. | Réblová K | Clinica chimica acta; international journal of clinical chemistry | 2013 | PMID: 23357515 |
| Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan. | Okano Y | Journal of human genetics | 2011 | PMID: 21307867 |
| Five human phenylalanine hydroxylase proteins identified in mild hyperphenylalaninemia patients are disease-causing variants. | Daniele A | Biochimica et biophysica acta | 2008 | PMID: 18346471 |
| 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 and phenotypic characteristics of patients with phenylketonuria in Serbia and Montenegro. | Stojiljkovic M | Clinical genetics | 2006 | PMID: 16879198 |
| Incidence of BH4-responsiveness in phenylalanine-hydroxylase-deficient Italian patients. | Fiori L | Molecular genetics and metabolism | 2005 | PMID: 16198137 |
| Mutational spectrum in German patients with phenylalanine hydroxylase deficiency. | Aulehla-Scholz C | Human mutation | 2003 | PMID: 12655553 |
| Should genetic analysis in newborn screening and a heterozygote test for hyperphenylalaninaemia be recommended? An Italian study. | Rottoli A | Journal of medical screening | 1999 | PMID: 10693064 |
| Mutational spectrum of phenylalanine hydroxylase deficiency in the population resident in Catalonia: genotype-phenotype correlation. | Mallolas J | Human genetics | 1999 | PMID: 10598814 |
| Phenylketonuria mutations in Germany. | Zschocke J | Human genetics | 1999 | PMID: 10394930 |
| Genetic and phenotypic aspects of phenylalanine hydroxylase deficiency in Spain: molecular survey by regions. | Desviat LR | European journal of human genetics : EJHG | 1999 | PMID: 10234516 |
| Molecular basis of mild hyperphenylalaninaemia in Poland. | Zekanowski C | Journal of medical genetics | 1997 | PMID: 9429153 |
| Mutations of the phenylalanine hydroxylase gene in mild hyperphenylalaninemia: a novel mutation in exon 3. | Zekanowski C | Human mutation | 1997 | PMID: 9298832 |
| DGGE analysis as supplement to SSCP analysis of the phenylalanine hydroxylase gene: detection of eight (one de novo, seven inherited) of nine remaining Norwegian PKU mutations. | Eiken HG | Human mutation | 1996 | PMID: 8807331 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/d5b91f03-15c0-4ffe-9fe6-2a8fca19096a | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs62642939 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 19, 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.