ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.1139C>T (p.Thr380Met)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000277.3(PAH):c.1139C>T (p.Thr380Met)
Variation ID: 628 Accession: VCV000000628.66
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q23.2 12: 102843706 (GRCh38) [ NCBI UCSC ] 12: 103237484 (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 Oct 8, 2024 Oct 1, 2018 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000277.3:c.1139C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000268.1:p.Thr380Met missense NM_001354304.2:c.1139C>T NP_001341233.1:p.Thr380Met missense NC_000012.12:g.102843706G>A NC_000012.11:g.103237484G>A NG_008690.2:g.119705C>T P00439:p.Thr380Met - Protein change
- T380M
- Other names
- p.T380M:ACG>ATG
- NM_000277.1(PAH):c.1139C>T
- Canonical SPDI
- NC_000012.12:102843705:G:A
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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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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Exome Aggregation Consortium (ExAC) 0.00033
The Genome Aggregation Database (gnomAD) 0.00036
Trans-Omics for Precision Medicine (TOPMed) 0.00037
The Genome Aggregation Database (gnomAD), exomes 0.00044
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 | ||
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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. |
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PAH | - | - |
GRCh38 GRCh37 |
1504 | 1627 |
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. |
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Pathogenic (1) |
no assertion criteria provided
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Jan 1, 1994 | RCV000000660.13 | |
Pathogenic (21) |
reviewed by expert panel
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Oct 1, 2018 | RCV000150077.57 | |
Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
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Nov 3, 2021 | RCV000078502.45 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Jan 31, 2021 | RCV000850463.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 2, 2020 | RCV001280537.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 12, 2023 | RCV003258654.9 | |
PAH-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Mar 23, 2024 | RCV003390629.6 |
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. |
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Pathogenic
(Oct 01, 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
FDA Recognized Database
Accession: SCV000852140.4 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
Comment:
The c.1139C>T (p.Thr380Met) variant in PAH has been reported in 1 patient with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 8268925). This variant has 28% … (more)
The c.1139C>T (p.Thr380Met) variant in PAH has been reported in 1 patient with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 8268925). This variant has 28% enzyme activity (PS3; PMID: 27620137). This variant was detected in trans with multiple known pathogenic variants: R408W, R261Q, I65T, F299C (PM3_Very-strong; PMID: 7981714). Computational prediction tools and conservation analysis suggest that the c.1139C>T variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3_Very-strong (less)
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Pathogenic
(Oct 08, 2014)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000744092.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
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Pathogenic
(Aug 08, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000110358.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 9
Sex: mixed
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Pathogenic
(Apr 27, 2017)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000375562.3
First in ClinVar: Dec 06, 2016 Last updated: May 27, 2019 |
Comment:
The PAH c.1139C>T (p.Thr380Met) missense variant has been reported in at least 14 studies in which it is found in a total of 24 patients … (more)
The PAH c.1139C>T (p.Thr380Met) missense variant has been reported in at least 14 studies in which it is found in a total of 24 patients with phenylalanine hydroxylase deficiency including in 19 in a compound heterozygous state, and five in a heterozygous state (Guldberg et al. 1993; Zschocke et al. 1994; Zschocke et al. 1995; Kayaalp et al. 1997; Zekanowski et al. 1997; Pérez et al. 1997; Tyfield et al. 1997; Guldberg et al. 1998; Yang et al. 2001; Ho et al. 2014; Liu et al 2015). The p.Thr380Met variant was found in 1.2 - 5% of alleles tested in subsequent studies of PAH deficiency (Desviat et al. 1999; Bercovich et al. 2008; Okano et al. 2011). Control data are unavailable for this variant from these studies, which is reported at a frequency of 0.0007 in the European American population of the Exome Sequencing Project. In functional studies by Heintz et al. (2012), the p.Thr380Met variant enzyme was shown to have a reduced activity of 38% compared to the wild type. This residual activity is consistent with the milder phenotype associated with this variant. The variant created a new exonic splice enhancer resulting in a stronger definition of exon 11 of the PAH gene, having a positive effect on splicing and the inclusion of exon 11. RNA affinity binding and Western blotting analysis showed that the p.Thr380Met variant abolished the normal binding of three splicing factors seen in the wild type. When found with a severe PAH variant, the p.Thr380Met variant is thought be involved in mild elevations of serum phenylalanine. These patients do not require dietary treatment. Based on the collective evidence, the p.Thr380Met variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Oct 17, 2018)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: yes
Allele origin:
paternal
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000966190.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
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Pathogenic
(Oct 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
paternal
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV001245020.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
Comment:
A heterozygous missense variant, NM_000277.1(PAH):c.1139C>T, has been identified in exon 11 of 13 of the PAH gene. The variant is predicted to result in a … (more)
A heterozygous missense variant, NM_000277.1(PAH):c.1139C>T, has been identified in exon 11 of 13 of the PAH gene. The variant is predicted to result in a moderate amino acid change from a threonine to a methionine at position 380 of the protein, NP_000268.1(PAH):p.(Thr380Met). The threonine residue at this position has high conservation (100 vertebrates, UCSC), and is located within the biopterin domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.04% (108 heterozygotes, 1 homozygote). The variant has previously been described multiple times as pathogenic in patients with phenylalanine hydroxylase deficiency (ClinVar). Additionally, patients with this variants were shown to have a reduced enzyme activity of 38% (Heintz, C., et al. (2012)). Analysis of parental samples indicated this variant was paternally inherited and to be present in cis with the second reported PAH variant. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
Number of individuals with the variant: 2
Clinical Features:
Hydrops fetalis (present) , Chylothorax (present) , Micrognathia (present)
Family history: yes
Secondary finding: yes
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Likely pathogenic
(May 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: yes
Allele origin:
unknown
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV001251673.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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Likely pathogenic
(Dec 20, 2019)
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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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Myriad Genetics, Inc.
Accession: SCV001193784.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000277.1(PAH):c.1139C>T(T380M) is classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 27620137, 22698810, 8830172, 10598814, … (more)
NM_000277.1(PAH):c.1139C>T(T380M) is classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 27620137, 22698810, 8830172, 10598814, 17096675, 23792259, 9012412, 10394930, 26666653, 27243974, 8533759, 26542770, 23357515, 12655553, 16198137, 9298832, 27121329, 14722928, 18294361, 18299955, 23500595, 8268925, 21307867, 9634518, 23932990, 10693064, 16198137, 8533759, 11385716, 22698810, 24350308, 17924342, 21147011 and 24368688. Classification of NM_000277.1(PAH):c.1139C>T(T380M) is based on the following criteria: This variant 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)
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Likely pathogenic
(Jul 21, 2021)
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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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Centogene AG - the Rare Disease Company
Accession: SCV002059727.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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Pathogenic
(Jun 14, 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: SCV000601707.3
First in ClinVar: Oct 09, 2016 Last updated: Dec 31, 2022 |
Comment:
This variant is associated with mild hyperphenylalaninemia when present with any other disease-causing variant in the PAH gene (PMIDs: 7981714 (1994), 8533759 (1995), 8268925 (1993), … (more)
This variant is associated with mild hyperphenylalaninemia when present with any other disease-causing variant in the PAH gene (PMIDs: 7981714 (1994), 8533759 (1995), 8268925 (1993), 18294361 (2008), 23500595 (2013), 26600521 (2015), 27121329 (2016), 33803550 (2021)), and is present in a significant percentage of individuals with PAH deficiency (PMIDs: 10234516 (1999), 21307867 (2011), and 27121329 (2016)). Additionally, multiple functional studies have indicated this variant has reduced activity compared to wild type and may affect splicing (PMIDs: 22698810 (2012) and 27620137 (2016)). (less)
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Pathogenic
(Dec 30, 2019)
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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: SCV000239086.13
First in ClinVar: Jul 18, 2015 Last updated: Mar 04, 2023 |
Comment:
Functional analysis demonstrates that T380M is associated with 38% of wildtype PAH enzyme activity (Heintz et al., 2012); This variant is associated with the following … (more)
Functional analysis demonstrates that T380M is associated with 38% of wildtype PAH enzyme activity (Heintz et al., 2012); This variant is associated with the following publications: (PMID: 26990548, 23500595, 23792259, 31355225, 12655544, 17935162, 25087612, 25333069, 8268925, 27620137, 22698810, 30337205, 30747360, 29731766, 31980526, 30275481, 31589614, 32668217) (less)
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Pathogenic
(Jan 31, 2024)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000629172.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 380 of the PAH protein (p.Thr380Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 380 of the PAH protein (p.Thr380Met). This variant is present in population databases (rs62642937, gnomAD 0.5%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with mild phenylketonuria (PKU) or mild hyperphenylalaninemia (HPA) (PMID: 8268925, 8533759, 9429153, 10598814, 14722928, 18299955, 23500595, 26600521, 26666653; 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: 628). 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: 22698810, 27620137). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Mar 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807930.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
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Pathogenic
(Jun 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848710.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Thr380Met variant in PAH has been reported in at least seven individuals with phenylalanine hydroxylase deficiency including six compound heterozygotes of which five have … (more)
The p.Thr380Met variant in PAH has been reported in at least seven individuals with phenylalanine hydroxylase deficiency including six compound heterozygotes of which five have pathogenic variants in trans as classified by the ClinGen PAH Variant Curation Expert Panel (Guldberg 1993 PMID: 8268925, Guo 2018 PMID: 29731766, Zschocke 1994 PMID: 7981714). It has also been identified in 0.52% (18/3472) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar as pathogenic by the ClinGen PAH Variant Curation Expert Panel using the . ACMG-AMP criteria specific for phenylalanine hydroxylase variants (Zastrow 2018 PMID: 30311390) and is curated in the FDA-recognized human genetic variant database (Variation ID 628). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function and decreases PAH activity to 28% (Trunzo 2016 PMID: 27620137); however, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive phenylalanine hydroxylase deficiency. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3, PP3, PP4_Moderate, BS1_Supporting. (less)
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Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: curation
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Phenylketonuria
Affected status: no
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051914.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
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Pathogenic
(Mar 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001163714.2
First in ClinVar: Mar 01, 2020 Last updated: Jun 17, 2024 |
|
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Pathogenic
(Jan 01, 2021)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001501014.22
First in ClinVar: Mar 14, 2021 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 1
|
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Likely pathogenic
(Jul 26, 2016)
|
criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745570.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
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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
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893267.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
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Pathogenic
(Dec 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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BH4-deficient hyperphenylalaninemia A
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696427.2
First in ClinVar: Oct 11, 2015 Last updated: Jan 09, 2021 |
Comment:
Variant summary: PAH c.1139C>T (p.Thr380Met) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded … (more)
Variant summary: PAH c.1139C>T (p.Thr380Met) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 251264 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Hyperphenylalaninemia (0.00044 vs 0.0079), allowing no conclusion about variant significance. c.1139C>T has been reported in the literature in multiple individuals affected with Hyperphenylalaninemia (example, Ho_2013, Zschocke_1995, Bercovich_2008, Guldberg_1998, Heintz_2012, Zekanowski_1997). 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 (Heintz_2012). The most pronounced variant effect results in 30%-50% of normal PAH activity. Multiple clinical diagnostic laboratories and one expert panel (ClinGen PAH Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jul 22, 2021)
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criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001810547.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
|
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Pathogenic
(May 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002521016.1
First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.042%). Missense changes are a common disease-causing mechanism. … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.042%). 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: 27620137). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 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 4 similarly affected unrelated individuals (PMID: 7981714). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Seizure (present)
|
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Uncertain significance
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009280.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
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Pathogenic
(Mar 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002016478.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Apr 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003983184.2
First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024 |
Comment:
The c.1139C>T (p.T380M) alteration is located in exon 11 (coding exon 11) of the PAH gene. This alteration results from a C to T substitution … (more)
The c.1139C>T (p.T380M) alteration is located in exon 11 (coding exon 11) of the PAH gene. This alteration results from a C to T substitution at nucleotide position 1139, causing the threonine (T) at amino acid position 380 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of 0.042% (118/282648) total alleles studied. The highest observed frequency was 0.473% (49/10364) of Ashkenazi Jewish alleles. This alteration was detected in the homozygous state and in conjunction with another alteration in PAH in multiple individuals with phenylalanine hydroxylase deficiency (Martín-Rivada, 2022; Odagiri,2021; Aldámiz-Echevarría, 2016; Bayat, 2016; Bercovich, 2008; Bercovich, 2008; Fiori, 2005; Mallolas, 1999, Zekanowski, 1997). This amino acid position is highly conserved in available vertebrate species. Functional assays show reduced enzyme activity in vitro (Heintz, 2012; Trunzo, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Jan 01, 1994)
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no assertion criteria provided
Method: literature only
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HYPERPHENYLALANINEMIA, NON-PKU
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020810.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 26, 2015 |
Comment on evidence:
Up to 10% of newborn children with a positive Guthrie test have non-phenylketonuria hyperphenylalaninemia (see PKU, 261600), i.e., mild elevation of serum phenylalanine that does … (more)
Up to 10% of newborn children with a positive Guthrie test have non-phenylketonuria hyperphenylalaninemia (see PKU, 261600), i.e., mild elevation of serum phenylalanine that does not require dietary treatment. Depending on the relative frequencies of different PAH mutations in a particular population, non-PKU hyperphenylalaninemia is usually caused by the combined effect of a mild hyperphenylalaninemia mutation and a severe PKU mutation. In a comprehensive analysis of non-PKU HPA in Northern Ireland, Zschocke et al. (1994) found that the thr380-to-met (T380M) mutation was present in over 70% of such cases. Screening for this mutation is easy and inexpensive and can help confirm the diagnosis of non-PKU HPA in most cases at an early stage. This should be clinically useful and reassuring for parents. (less)
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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
|
Natera, Inc.
Accession: SCV001463119.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Phenylketonuria
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552997.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The PAH c.1139C>T (p.Thr380Met) missense variant has been reported in at least 14 studies in which it is found in a total of 24 patients … (more)
The PAH c.1139C>T (p.Thr380Met) missense variant has been reported in at least 14 studies in which it is found in a total of 24 patients with phenylalanine hydroxylase deficiency including in 19 in a compound heterozygous state, and five in a heterozygous state (Guldberg et al. 1993; Zschocke et al. 1994; Zschocke et al. 1995; Kayaalp et al. 1997; Zekanowski et al. 1997; Pérez et al. 1997; Tyfield et al. 1997; Guldberg et al. 1998; Yang et al. 2001; Ho et al. 2014; Liu et al 2015). The p.Thr380Met variant was found in 1.2 - 5% of alleles tested in subsequent studies of PAH deficiency (Desviat et al. 1999; Bercovich et al. 2008; Okano et al. 2011). Control data are unavailable for this variant from these studies, which is reported at a frequency of 0.0007 in the European American population of the Exome Sequencing Project. In functional studies by Heintz et al. (2012), the p.Thr380Met variant enzyme was shown to have a reduced activity of 38% compared to the wild type. This residual activity is consistent with the milder phenotype associated with this variant. The variant created a new exonic splice enhancer resulting in a stronger definition of exon 11 of the PAH gene, having a positive effect on splicing and the inclusion of exon 11. RNA affinity binding and Western blotting analysis showed that the p.Thr380Met variant abolished the normal binding of three splicing factors seen in the wild type. When found with a severe PAH variant, the p.Thr380Met variant is thought be involved in mild elevations of serum phenylalanine. These patients do not require dietary treatment. The variant was identified in dbSNP (rs62642937) and ClinVar (classified as pathogenic by multiple sources) databases. The variant was identified in control databases in 181 of 282,648 alleles (1 homozygous) at a frequency of 0.04%, and was observed at the highest frequency in the Ashkenazi Jewish population in 10,364 of 282,648 alleles (freq: 0.47%) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.Thr380Met residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. Based on the collective evidence, the p.Thr380Met variant is classified as pathogenic for phenylalanine hydroxylase deficiency. (less)
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Pathogenic
(Mar 23, 2024)
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no assertion criteria provided
Method: clinical testing
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PAH-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004110233.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The PAH c.1139C>T variant is predicted to result in the amino acid substitution p.Thr380Met. This variant has been reported in multiple studies as causative for … (more)
The PAH c.1139C>T variant is predicted to result in the amino acid substitution p.Thr380Met. This variant has been reported in multiple studies as causative for mild hyperphenylalaninemia (HPA) when in the compound heterozygous state with a second causative PAH variant (e.g., Mallolas et al. 1999. PubMed ID: 10598814; Bercovich et al. 2008. PubMed ID: 18299955; Heintz et al. 2012. PubMed ID: 22698810; Aldámiz-Echevarría et al. 2016. PubMed ID: 27121329). In in vitro expression assays, the p.Thr380Met substitution reduced the activity of the PAH enzyme to ~28-38% of control (Heintz et al. 2012. PubMed ID: 22698810; Trunzo et al. 2016. PubMed ID: 27620137). The p.Thr380Met amino acid substitution has been reported to result in a mutant PAH protein that is responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). The c.1139C>T variant has been reported at an allele frequency of 0.46%, including 1 homozygous individual, in an Ashkenazi Jewish population; in other populations, it is observed less frequently (i.e., <0.1%). This variant is classified as pathogenic in the ClinVar database by the ClinGen PAH Variant Curation Expert Panel and multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/628/). In summary, this variant is classified as pathogenic. (less)
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Pathogenic
(May 19, 2016)
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no assertion criteria provided
Method: research
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
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Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536867.1 First in ClinVar: Apr 22, 2017 Last updated: Apr 22, 2017 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958930.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 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: SCV000119353.1
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
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Uncertain significance
(-)
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Flagged submission
flagged submission
Method: research
Reason: Claim with insufficient supporting evidence
Source: ClinGen
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Marfanoid habitus and intellectual disability
Affected status: yes
Allele origin:
de novo
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000992661.1
First in ClinVar: Sep 23, 2019 Last updated: Sep 23, 2019 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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 |
---|---|---|---|---|
Diagnosis of inborn errors of metabolism within the expanded newborn screening in the Madrid region. | Martín-Rivada Á | JIMD reports | 2022 | PMID: 35281663 |
Clinical and Genetic Characteristics of Patients with Mild Hyperphenylalaninemia Identified by Newborn Screening Program in Japan. | Odagiri S | International journal of neonatal screening | 2021 | PMID: 33803550 |
Frequency spectrum of rare and clinically relevant markers in multiethnic Indian populations (ClinIndb): A resource for genomic medicine in India. | Narang A | Human mutation | 2020 | PMID: 32906206 |
In vitro residual activity of phenylalanine hydroxylase variants and correlation with metabolic phenotypes in PKU. | Trunzo R | Gene | 2016 | PMID: 27620137 |
Targeted Next Generation Sequencing in Patients with Inborn Errors of Metabolism. | Yubero D | PloS one | 2016 | PMID: 27243974 |
Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria. | Aldámiz-Echevarría L | Journal of human genetics | 2016 | PMID: 27121329 |
Mutational and phenotypical spectrum of phenylalanine hydroxylase deficiency in Denmark. | Bayat A | Clinical genetics | 2016 | PMID: 26542770 |
Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness. | Jeannesson-Thivisol E | Orphanet journal of rare diseases | 2015 | PMID: 26666653 |
Prenatal diagnosis of Chinese families with phenylketonuria. | Liu N | Genetics and molecular research : GMR | 2015 | PMID: 26600521 |
Disease variants in genomes of 44 centenarians. | Freudenberg-Hua Y | Molecular genetics & genomic medicine | 2014 | PMID: 25333069 |
Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results. | Tabor HK | American journal of human genetics | 2014 | PMID: 25087612 |
The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness. | Ho G | JIMD reports | 2014 | PMID: 24368688 |
Molecular genetics of PKU in Poland and potential impact of mutations on BH4 responsiveness. | Bik-Multanowski M | Acta biochimica Polonica | 2013 | PMID: 24350308 |
Variations in genotype-phenotype correlations in phenylalanine hydroxylase deficiency in Chinese Han population. | Zhu T | Gene | 2013 | PMID: 23932990 |
Mutation analysis in hyperphenylalaninemia patients from South Italy. | Trunzo R | Clinical biochemistry | 2013 | PMID: 23792259 |
Molecular epidemiology and BH4-responsiveness in patients with phenylalanine hydroxylase deficiency from Galicia region of Spain. | Couce ML | Gene | 2013 | PMID: 23500595 |
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 |
Splicing of phenylalanine hydroxylase (PAH) exon 11 is vulnerable: molecular pathology of mutations in PAH exon 11. | Heintz C | Molecular genetics and metabolism | 2012 | PMID: 22698810 |
Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan. | Okano Y | Journal of human genetics | 2011 | PMID: 21307867 |
Molecular genetics and impact of residual in vitro phenylalanine hydroxylase activity on tetrahydrobiopterin responsiveness in Turkish PKU population. | Dobrowolski SF | Molecular genetics and metabolism | 2011 | PMID: 21147011 |
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 |
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 |
Incidence of BH4-responsiveness in phenylalanine-hydroxylase-deficient Italian patients. | Fiori L | Molecular genetics and metabolism | 2005 | PMID: 16198137 |
Mutation spectrum in Taiwanese patients with phenylalanine hydroxylase deficiency and a founder effect for the R241C mutation. | Chien YH | Human mutation | 2004 | PMID: 14722928 |
Mutational spectrum in German patients with phenylalanine hydroxylase deficiency. | Aulehla-Scholz C | Human mutation | 2003 | PMID: 12655553 |
Molecular analysis of phenylketonuria (PKU) in newborns from Texas. | Yang Y | Human mutation | 2001 | PMID: 11385716 |
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 |
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 |
Molecular basis of mild hyperphenylalaninaemia in Poland. | Zekanowski C | Journal of medical genetics | 1997 | PMID: 9429153 |
Human phenylalanine hydroxylase mutations and hyperphenylalaninemia phenotypes: a metanalysis of genotype-phenotype correlations. | Kayaalp E | American journal of human genetics | 1997 | PMID: 9399896 |
Mutations of the phenylalanine hydroxylase gene in mild hyperphenylalaninemia: a novel mutation in exon 3. | Zekanowski C | Human mutation | 1997 | PMID: 9298832 |
Sequence variation at the phenylalanine hydroxylase gene in the British Isles. | Tyfield LA | American journal of human genetics | 1997 | PMID: 9012412 |
Analysis of the phenylalanine hydroxylase gene in the Spanish population: mutation profile and association with intragenic polymorphic markers. | Pérez B | American journal of human genetics | 1997 | PMID: 8981952 |
PAH deficiency in Italy: correlation of genotype with phenotype in the Sicilian population. | Romano V | Journal of inherited metabolic disease | 1996 | PMID: 8830172 |
Phenylketonuria mutation analysis in Northern Ireland: a rapid stepwise approach. | Zschocke J | American journal of human genetics | 1995 | PMID: 8533759 |
Non-phenylketonuria hyperphenylalaninaemia in Northern Ireland: frequent mutation allows screening and early diagnosis. | Zschocke J | Human mutation | 1994 | PMID: 7981714 |
Mutational spectrum of phenylalanine hydroxylase deficiency in Sicily: implications for diagnosis of hyperphenylalaninemia in southern Europe. | Guldberg P | Human molecular genetics | 1993 | PMID: 8268925 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/95c70134-5e17-4767-a5b4-84155f4374bd | - | - | - | - |
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Text-mined citations for rs62642937 ...
HelpRecord last updated Oct 08, 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.