ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.842C>T (p.Pro281Leu)
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
-
NM_000277.3(PAH):c.842C>T (p.Pro281Leu)
Variation ID: 589 Accession: VCV000000589.113
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q23.2 12: 102852815 (GRCh38) [ NCBI UCSC ] 12: 103246593 (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 May 1, 2024 Aug 27, 2018 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000277.3:c.842C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000268.1:p.Pro281Leu missense NM_001354304.2:c.842C>T NP_001341233.1:p.Pro281Leu missense NC_000012.12:g.102852815G>A NC_000012.11:g.103246593G>A NG_008690.2:g.110596C>T P00439:p.Pro281Leu - Protein change
- P281L
- Other names
- NM_000277.1(PAH):c.842C>T
- Canonical SPDI
- NC_000012.12:102852814:G:A
-
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) 0.00010
The Genome Aggregation Database (gnomAD) 0.00010
The Genome Aggregation Database (gnomAD), exomes 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00015
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. |
|||
PAH | - | - |
GRCh38 GRCh37 |
1486 | 1605 |
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. |
---|---|---|---|---|
Likely pathogenic (18) |
reviewed by expert panel
|
Aug 27, 2018 | RCV000000620.106 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jun 1, 2022 | RCV000078534.35 | |
Pathogenic (1) |
criteria provided, single submitter
|
May 21, 2021 | RCV001265833.12 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jan 2, 2024 | RCV003914790.1 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Aug 27, 2018)
|
reviewed by expert panel
Method: curation
|
Phenylketonuria
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen PAH Variant Curation Expert Panel
Accession: SCV000852092.4
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
Comment:
PAH-specific ACMG/AMP criteria applied: PP3: ; PS3: 2% activity in bioPKU (PAH0309) (PMID:25596310; PMID:17935162); PP4_Moderate: 2 patients with moderate or classical PKU; patients with severe … (more)
PAH-specific ACMG/AMP criteria applied: PP3: ; PS3: 2% activity in bioPKU (PAH0309) (PMID:25596310; PMID:17935162); PP4_Moderate: 2 patients with moderate or classical PKU; patients with severe PKU. BH4 deficiency ruled out. (PMID:15503242; PMID:12655553); PM3: IVS4-1G>A (P/LP) (PMID:15503242). In summary this variant meets criteria to be classified as likely 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). (less)
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Phenylketonuria
Affected status: yes
Allele origin:
germline
|
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251474.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
The PAH c.842C>T (p.P281L) variant is located at an intron/exon boundary, and this variant has been reported as pathogenic in individuals with phenylketonuria. This variant … (more)
The PAH c.842C>T (p.P281L) variant is located at an intron/exon boundary, and this variant has been reported as pathogenic in individuals with phenylketonuria. This variant was also shown to abolish the function of the phenylalanine hydroxylase enzyme in vitro (PMID: 1672290; 9634518; 10234516; 17935162). (less)
Number of individuals with the variant: 2
|
|
Pathogenic
(Nov 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003826584.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000629222.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 281 of the PAH protein (p.Pro281Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 281 of the PAH protein (p.Pro281Leu). This variant is present in population databases (rs5030851, gnomAD 0.02%). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 1672294, 21871829, 25596310; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 589). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PAH function (PMID: 1672294, 17935162, 21953985). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Jan 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
PAH-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004735001.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The PAH c.842C>T variant is predicted to result in the amino acid substitution p.Pro281Leu. This variant is a recurrent variant that has been documented as … (more)
The PAH c.842C>T variant is predicted to result in the amino acid substitution p.Pro281Leu. This variant is a recurrent variant that has been documented as causative for phenylalanine hydroxylase deficiency and has been associated with classical phenylketonuria (PKU) (e.g., Okano et al. 1991. PubMed ID: 2014036; Ellingsen et al. 1999, PubMed ID: 10471838; Trunzo et al. 2014, PubMed ID: 24296287; Hillert et al. 2020. PubMed ID: 32668217). The p.Pro281 amino acid resides in the cofactor binding site (CBR) region of the PAH enzyme, and the p.Pro281Leu substitution has been reported to reduce enzyme activity to ~1% of control and result in a mutant PAH protein that is non-responsive to BH4 (Zurflüh et al. 2008. PubMed ID: 17935162). This variant is classified as pathogenic or likely pathogenic by multiple outside laboratories, as well as the ClinGen PAH Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/589/). This variant is interpreted as pathogenic. (less)
|
|
Pathogenic
(Jun 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249178.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Comment:
PAH: PM3:Very Strong, PM1, PM2, PM5, PP3, PS3:Supporting
Number of individuals with the variant: 4
|
|
Pathogenic
(Dec 29, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847976.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Pro281Leu variant in PAH was first reported in patients with classic PKU by Okano et al., (Okano 1991, Okano 1991) and has been reported … (more)
The p.Pro281Leu variant in PAH was first reported in patients with classic PKU by Okano et al., (Okano 1991, Okano 1991) and has been reported in numerous patients with PKU since then (Zurfluh 2008, Danecka 2015). In vitro functional studies provide evidence that the p.Pro281Leu variant impacts protein function (Okano 1991, Zurfluh 2008, Danecka 2015, Ellingsen 1999, Reblova 2015, Shi 2012). This variant has been identified in 0.018% (12/66740) of Euroepan chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; rs5030851). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant meets our criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner. (less)
|
|
Pathogenic
(Jan 19, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696468.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
Variant summary: The PAH c.842C>T (p.Pro281Leu) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant, … (more)
Variant summary: The PAH c.842C>T (p.Pro281Leu) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant, which was confirmed by at least one in vitro study showing the activity of PAH p.P281L was <1% of wild-type PAH activity (Kayaalp_1997). This variant was found in 12/121404 control chromosomes at a frequency of 0.0000988, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant has been reported in numerous patients with classic PKU. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
Pathogenic
(Jan 26, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000110390.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 16
Sex: mixed
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893941.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163718.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
|
|
Pathogenic
(Dec 04, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001193964.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000277.1(PAH):c.842C>T(P281L) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 22513348, 22526846, 19394257, 15503242, 20920871, … (more)
NM_000277.1(PAH):c.842C>T(P281L) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 22513348, 22526846, 19394257, 15503242, 20920871, 20187763, 22763404, 18299955, 17935162 and 10471838. Classification of NM_000277.1(PAH):c.842C>T(P281L) 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. (less)
|
|
Pathogenic
(Jan 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440177.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
Comment:
This variant was identified as compound heterozygous.
|
|
Pathogenic
(Jul 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001810543.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
|
|
Pathogenic
(May 18, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329448.5
First in ClinVar: Dec 06, 2016 Last updated: Dec 19, 2017 |
Comment:
Associated with very low (0-1%) residual phenylalanine hydroxylase enzyme activity and is considered a severe PAH variant as individuals homozygous for this variant have been … (more)
Associated with very low (0-1%) residual phenylalanine hydroxylase enzyme activity and is considered a severe PAH variant as individuals homozygous for this variant have been reported with classic phenylketonuria (Okano et al., 1991; Rivera et al., 2011; Shi et al., 2012; Danecka et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported to not be responsive to tetrahydrobiopterin (BH4) therapy (Zurflh et al., 2008); This variant is associated with the following publications: (PMID: 33101986, 31589614, 32853555, 30275481, 30747360, 31355225, 30648773, 30963030, 30159272, 12501224, 24296287, 21871829, 29288420, 1672294, 29499199, 2014036, 28676969, 19194782, 22513348, 8889590, 1672290, 25750018, 17935162, 1481864, 21953985, 25596310, 25087612, 22975760, 21228398, 10471838) (less)
|
|
Likely pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058848.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000589, PMID:1672294, PS1_S). A … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000589, PMID:1672294, PS1_S). A different missense change at the same codon has been reported to be associated with PAH related disorder (ClinVar ID: VCV000092749, PMID:12409276,10598814,15171997, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.983, 3CNET: 0.998, PP3_P). A missense variant is a common mechanism associated with Classic phenylketonuria (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000103, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Autistic behavior (present)
|
|
Pathogenic
(Nov 03, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV002059760.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
|
|
Pathogenic
(Nov 04, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001470579.3
First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024 |
Comment:
In the literature, this variant has been reported as homozygous or compound heterozygous with other pathogenic PAH variants in many individuals with PAH-related diseases (PMIDs: … (more)
In the literature, this variant has been reported as homozygous or compound heterozygous with other pathogenic PAH variants in many individuals with PAH-related diseases (PMIDs: 30747360 (2019), 29749107 (2018), 25596310 (2015), 21871829 (2011), 20082265 (2010), 18294361 (2008), and 1672294 (1991)). An in vitro study indicated that the homozygous c.842C>T (p.Pro281Leu) variant could generate a full length splicing product and a shorter splicing product without exon 8. The full length product has minimal enzyme activity and the shorter product causes the premature termination of the PAH protein (PMID 10471838 (1999)). Multiple other experimental studies have also confirmed that this variant results in diminished enzyme activity and protein expression (PMID: 25596310 (2015), 21953985 (2012), 17935162 (2008), 11161839 (2001), and 1672294 (1991)). This pathogenic variant is located in the catalytic domain of the PAH protein and is associated with classic PKU (PMID 20082265 (2010)). (less)
|
|
Pathogenic
(Nov 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004244480.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
PS3, PM3_Strong, PP3
|
|
Pathogenic
(May 21, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001444005.4
First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024 |
Comment:
The c.842C>T (p.P281L) alteration is located in exon 7 (coding exon 7) of the PAH gene. This alteration results from a C to T substitution … (more)
The c.842C>T (p.P281L) alteration is located in exon 7 (coding exon 7) of the PAH gene. This alteration results from a C to T substitution at nucleotide position 842, causing the proline (P) at amino acid position 281 to be replaced by a leucine (L). Based on data from the Genome Aggregation Database (gnomAD) database, the PAH c.842C>T alteration was observed in 0.01% (29/282652) of total alleles studied, with a frequency of 0.02% (26/128978) in the European (non-Finnish) subpopulation. This mutation has been identified in numerous individuals with phenylalanine hydroxylase (PAH) deficiency (Okano, 1991; Shi, 2012; Gundorova, 2019) Activity and protein levels were approximately 1% when this variant was expressed n COS cells (Shi, 2012) The p.P281L alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
Pathogenic
(Jan 01, 1994)
|
no assertion criteria provided
Method: literature only
|
PHENYLKETONURIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020770.68
First in ClinVar: Apr 04, 2013 Last updated: May 01, 2024 |
Comment on evidence:
The pro281-to-leu (P281L) mutation in exon 7 was found on haplotype 1 in an Italian patient with phenylketonuria (PKU; 261600) (Okano et al., 1991). cDNA … (more)
The pro281-to-leu (P281L) mutation in exon 7 was found on haplotype 1 in an Italian patient with phenylketonuria (PKU; 261600) (Okano et al., 1991). cDNA carrying the mutation was constructed and transfected into cultured mammalian cells. Expression analysis revealed negligible enzyme activity and undetectable levels of immunoreactive PAH protein. This mutation, like the arg252-to-trp mutation (R252W; 612349.0007), is in marked linkage disequilibrium with RFLP haplotype 1. The P281L mutation was found on 20% of haplotype 1 mutant chromosomes in the Italian population (Okano et al., 1991). Dworniczak et al. (1991) found this mutation on 25% of all mutant haplotype 1 alleles in the German population. In addition, they identified this mutation on 1 mutant haplotype 4 allele. Expression analysis of the mutant allele in cultured mammalian cells demonstrated absence of immunoreactive PAH in cells transfected with this missense mutation, identical steady-state levels of mRNA in cells carrying both normal and mutant constructs, and absence of PAH activity in cells transfected with the mutant allele. Baric et al. (1994) pointed to data indicating that the highest frequency of the P281L mutation is in Croatia where it was detected in 55% of haplotype 1 alleles, corresponding to 12% of all PKU alleles. They interpreted this finding as indicating that the mutation originated in southeastern Europe. (less)
|
|
Pathogenic
(Mar 01, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Phenylketonuria
Affected status: no
Allele origin:
germline
|
Payam Genetics Center, General Welfare Department of North Khorasan Province
Accession: SCV003842177.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Number of individuals with the variant: 2
Sex: mixed
Ethnicity/Population group: Iranian
Geographic origin: Iran
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001453099.1
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: SCV000119744.1
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Phenylketonuria
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000324889.2
First in ClinVar: Oct 23, 2016 Last updated: Oct 01, 2022 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Mutation spectrum of PAH gene in phenylketonuria patients in Northwest China: identification of twenty novel variants. | Yan Y | Metabolic brain disease | 2019 | PMID: 30747360 |
Genotypes of 2579 patients with phenylketonuria reveal a high rate of BH4 non-responders in Russia. | Gundorova P | PloS one | 2019 | PMID: 30668579 |
Mutation analysis of the PAH gene in phenylketonuria patients from Rio de Janeiro, Southeast Brazil. | Vieira Neto E | Molecular genetics & genomic medicine | 2018 | PMID: 29749107 |
The complete European guidelines on phenylketonuria: diagnosis and treatment. | van Wegberg AMJ | Orphanet journal of rare diseases | 2017 | PMID: 29025426 |
Phenylalanine Hydroxylase Deficiency. | Adam MP | - | 2017 | PMID: 20301677 |
Mapping the functional landscape of frequent phenylalanine hydroxylase (PAH) genotypes promotes personalised medicine in phenylketonuria. | Danecka MK | Journal of medical genetics | 2015 | PMID: 25596310 |
Mutation analysis in hyperphenylalaninemia patients from South Italy. | Trunzo R | Clinical biochemistry | 2013 | PMID: 23792259 |
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 |
Prevalence of tetrahydrobiopterine (BH4)-responsive alleles among Austrian patients with PAH deficiency: comprehensive results from molecular analysis in 147 patients. | Sterl E | Journal of inherited metabolic disease | 2013 | PMID: 22526846 |
Mutation spectrum of the PAH gene in the PKU patients from Khorasan Razavi province of Iran. | Hamzehloei T | Gene | 2012 | PMID: 22763404 |
Five novel mutations and two large deletions in a population analysis of the phenylalanine hydroxylase gene. | Groselj U | Molecular genetics and metabolism | 2012 | PMID: 22513348 |
Protein stability and in vivo concentration of missense mutations in phenylalanine hydroxylase. | Shi Z | Proteins | 2012 | PMID: 21953985 |
Clinical utility gene card for: Phenylketonuria. | Zschocke J | European journal of human genetics : EJHG | 2012 | PMID: 21915151 |
Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. | Blau N | Molecular genetics and metabolism | 2011 | PMID: 21937252 |
Phenylalanine hydroxylase deficiency: molecular epidemiology and predictable BH4-responsiveness in South Portugal PKU patients. | Rivera I | Molecular genetics and metabolism | 2011 | PMID: 21871829 |
Mutation spectrum of phenylketonuria in Iranian population. | Zare-Karizi Sh | Molecular genetics and metabolism | 2011 | PMID: 20920871 |
Mutations of the phenylalanine hydroxylase gene in Iranian Azeri Turkish patients with phenylketonuria. | Bonyadi M | Genetic testing and molecular biomarkers | 2010 | PMID: 20187763 |
Variations in genotype-phenotype correlations in phenylketonuria patients. | Santos LL | Genetics and molecular research : GMR | 2010 | PMID: 20082265 |
Genotype-predicted tetrahydrobiopterin (BH4)-responsiveness and molecular genetics in Croatian patients with phenylalanine hydroxylase (PAH) deficiency. | Karacić I | Molecular genetics and metabolism | 2009 | PMID: 19394257 |
Genotype-phenotype correlations analysis of mutations in the phenylalanine hydroxylase (PAH) gene. | Bercovich D | Journal of human genetics | 2008 | PMID: 18299955 |
A mutation analysis of the phenylalanine hydroxylase (PAH) gene in the Israeli population. | Bercovich D | Annals of human genetics | 2008 | PMID: 18294361 |
Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. | Zurflüh MR | Human mutation | 2008 | PMID: 17935162 |
The molecular basis of phenylketonuria in Koreans. | Lee DH | Journal of human genetics | 2004 | PMID: 15503242 |
Structural studies on phenylalanine hydroxylase and implications toward understanding and treating phenylketonuria. | Erlandsen H | Pediatrics | 2003 | PMID: 14654665 |
Mutational spectrum in German patients with phenylalanine hydroxylase deficiency. | Aulehla-Scholz C | Human mutation | 2003 | PMID: 12655553 |
Two novel genetic lesions and a common BH4-responsive mutation of the PAH gene in Italian patients with hyperphenylalaninemia. | Bardelli T | Molecular genetics and metabolism | 2002 | PMID: 12409276 |
In vitro expression of 34 naturally occurring mutant variants of phenylalanine hydroxylase: correlation with metabolic phenotypes and susceptibility toward protein aggregation. | Gjetting T | Molecular genetics and metabolism | 2001 | PMID: 11161839 |
Diverse PAH transcripts in lymphocytes of PKU patients with putative nonsense (G272X, Y356X) and missense (P281L, R408Q) mutations. | Ellingsen S | FEBS letters | 1999 | PMID: 10471838 |
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 |
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 |
Human phenylalanine hydroxylase mutations and hyperphenylalaninemia phenotypes: a metanalysis of genotype-phenotype correlations. | Kayaalp E | American journal of human genetics | 1997 | PMID: 9399896 |
Geographical distribution of the P281L mutation at the phenylalanine hydroxylase locus: possible origin in southeastern Europe. | Barić I | Journal of inherited metabolic disease | 1994 | PMID: 7807961 |
A prevalent missense mutation in Northern Europe associated with hyperphenylalaninaemia. | Okano Y | European journal of pediatrics | 1991 | PMID: 2044609 |
Molecular basis of phenotypic heterogeneity in phenylketonuria. | Okano Y | The New England journal of medicine | 1991 | PMID: 2014036 |
Aberrant splicing of phenylalanine hydroxylase mRNA: the major cause for phenylketonuria in parts of southern Europe. | Dworniczak B | Genomics | 1991 | PMID: 1769645 |
Phenylketonuria missense mutations in the Mediterranean. | Okano Y | Genomics | 1991 | PMID: 1672294 |
Classical phenylketonuria in Bulgaria: RFLP haplotypes and frequency of the major mutations. | Kalaydjieva L | Journal of medical genetics | 1990 | PMID: 1981599 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c12aac5a-a84d-4ecc-b66a-d375bf2deb7b | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs5030851 ...
HelpRecord last updated May 01, 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.