ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.898G>T (p.Ala300Ser)
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.898G>T (p.Ala300Ser)
Variation ID: 92751 Accession: VCV000092751.115
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q23.2 12: 102851701 (GRCh38) [ NCBI UCSC ] 12: 103245479 (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 May 12, 2024 Aug 10, 2018 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000277.3:c.898G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000268.1:p.Ala300Ser missense NM_000277.2:c.898G>T NM_001354304.2:c.898G>T NP_001341233.1:p.Ala300Ser missense NC_000012.12:g.102851701C>A NC_000012.11:g.103245479C>A NG_008690.2:g.111710G>T P00439:p.Ala300Ser - Protein change
- A300S
- Other names
- p.A300S:GCC>TCC
- NM_000277.1(PAH):c.898G>T
- Canonical SPDI
- NC_000012.12:102851700:C: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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-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031
The Genome Aggregation Database (gnomAD) 0.00034
Trans-Omics for Precision Medicine (TOPMed) 0.00039
Exome Aggregation Consortium (ExAC) 0.00045
The Genome Aggregation Database (gnomAD), exomes 0.00059
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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LOC126861615 | - | - | - | GRCh38 | - | 84 |
PAH | - | - |
GRCh38 GRCh37 |
1488 | 1607 |
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 (8) |
criteria provided, multiple submitters, no conflicts
|
Oct 1, 2023 | RCV000078536.38 | |
Pathogenic (20) |
reviewed by expert panel
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Aug 10, 2018 | RCV000150084.55 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 9, 2016 | RCV000590551.9 | |
Pathogenic (1) |
criteria provided, single submitter
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May 9, 2022 | RCV001267463.12 |
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
(Aug 10, 2018)
|
reviewed by expert panel
Method: curation
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Phenylketonuria
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen PAH Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV000852126.4 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
Comment:
PAH-specific ACMG/AMP criteria applied: PP3: Deleterious in SIFT, Polyphen2, MutationTaster; PP4_Moderate: A300S found on 56/588 hyperphenylalaninemic patients, BH4 deficiency excluded. Upgraded per ClinGen Metabolic WG. … (more)
PAH-specific ACMG/AMP criteria applied: PP3: Deleterious in SIFT, Polyphen2, MutationTaster; PP4_Moderate: A300S found on 56/588 hyperphenylalaninemic patients, BH4 deficiency excluded. Upgraded per ClinGen Metabolic WG. (PMID:21147011); PM3_VeryStrong: Detected with c.1066-11G>A (P), R261Q(P/LP), L48S (P), R176X (P) in 20 patients. (PMID:21147011); PS3: A300S in vitro PAH activity of 31% (PMID:17935162). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PP4_Moderate, PM3_VeryStrong, PS3). (less)
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Pathogenic
(Jun 09, 2016)
|
criteria provided, single submitter
Method: clinical testing
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Hyperphenylalaninemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696470.1
First in ClinVar: Mar 20, 2018 Last updated: Mar 20, 2018 |
Comment:
Variant summary: The PAH c.898G>T (p.Ala300Ser) variant involves the alteration of a conserved nucleotide within the catalytic domain. 4/5 in silico tools predict a damaging … (more)
Variant summary: The PAH c.898G>T (p.Ala300Ser) variant involves the alteration of a conserved nucleotide within the catalytic domain. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 54/121010 control chromosomes at a frequency of 0.0004462, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant has been reported as one of the most common pathogenic variants that associate with a milder phenotype, which is consistant with the finding that p.Ala300Ser retains 31% of enzyme activity (Zurfluh_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Jun 16, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000110392.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 21
Sex: mixed
|
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Pathogenic
(-)
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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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Baylor Genetics
Accession: SCV001163717.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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Pathogenic
(Dec 26, 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: SCV001194112.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000277.1(PAH):c.898G>T(A300S) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and may be associated with classic, variant, or non-PKU hyperphenylalaninemia. Sources cited for … (more)
NM_000277.1(PAH):c.898G>T(A300S) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and may be associated with classic, variant, or non-PKU hyperphenylalaninemia. Sources cited for classification include the following: PMID 9298832, 18538294, 23500595, 18299955, 16198137, 21147011, 15557004, 23792259, 24350308, and 17935162. Classification of NM_000277.1(PAH):c.898G>T(A300S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Jul 30, 2019)
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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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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368400.2
First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM5,PP2,PP3,PP5.
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Pathogenic
(Jul 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001810539.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Pathogenic
(Oct 04, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889565.2
First in ClinVar: Dec 15, 2018 Last updated: Jan 03, 2022 |
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Pathogenic
(Mar 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
inherited
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002099014.1 First in ClinVar: Feb 26, 2022 Last updated: Feb 26, 2022 |
Clinical Features:
Intellectual disability (present) , Seizure (present) , Global developmental delay (present) , Coarse facial features (present) , Prominent forehead (present) , Hypotonia (present) , Violent … (more)
Intellectual disability (present) , Seizure (present) , Global developmental delay (present) , Coarse facial features (present) , Prominent forehead (present) , Hypotonia (present) , Violent behavior (present) , Receptive language delay (present) , Expressive language delay (present) (less)
Secondary finding: no
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Pathogenic
(Jan 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579859.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PM3_STR, PP4_MOD, PP3
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Number of individuals with the variant: 2
Sex: male
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Pathogenic
(Aug 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556614.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Apr 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002016470.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 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
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967677.2
First in ClinVar: Aug 26, 2019 Last updated: Apr 20, 2024 |
Comment:
The p.Ala300Ser variant in PAH is a well-established pathogenic variant in patients with phenylketonuria (Trefz 2009 PMID: 18956252, Heintz 2013 PMID: 23559577, Danecka 2015 PMID: … (more)
The p.Ala300Ser variant in PAH is a well-established pathogenic variant in patients with phenylketonuria (Trefz 2009 PMID: 18956252, Heintz 2013 PMID: 23559577, Danecka 2015 PMID: 25596310), and is frequently associated with milder course and responsiveness to BH4 (Trefz 2009 PMID: 18956252, Heintz 2013 PMID: 23559577). In vitro functional studies provide some evidence that the p.Ala300Ser variant impacts protein function (Shen 2016 PMID: 26803807). This variant has been identified in 0.6% (67/10130) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs5030853). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis suggest that the p.Ala300Ser variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for phenylalanine hydroxylase deficiency in an autosomal recessive manner. ACMG/AMP Criteria applied PS3; PS4; PP3. (less)
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Pathogenic
(May 09, 2022)
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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: SCV001445644.4
First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024 |
Comment:
The c.898G>T (p.A300S) alteration is located in coding exon 8 of the PAH gene. This alteration results from a G to T substitution at nucleotide … (more)
The c.898G>T (p.A300S) alteration is located in coding exon 8 of the PAH gene. This alteration results from a G to T substitution at nucleotide position 898, causing the alanine (A) at amino acid position 300 to be replaced by a serine (S). Based on data from gnomAD, the T allele has an overall frequency of 0.05% (152/282410) total alleles studied. The highest observed frequency was 0.69% (71/10350) of Ashkenazi Jewish alleles. This alteration has been reported in individuals both homozygous and compound heterozygous with a second disease-causing allele and is typically associated with mild PKU or hyperphenylalaninemia (Bercovich, 2008; Dobrowolski, 2011; Couce, 2013; Réblová, 2013; Trunzo, 2013; Danecka, 2015; Jeannesson-Thivisol, 2015). Multiple studies have found that patients with this alteration are BH4-responsive (Zurflüh, 2008; Jeannesson-Thivisol, 2015; Shen, 2016). This amino acid position is highly conserved in available vertebrate species. The p.A300 amino acid is located in the catalytic domain of the protein. The serine substitution is too large for the side chain and destabilization is due to the change of polarity of the catalytic domain's core (reviewed in Blau, 2004). Functional analysis demonstrated the p.A300S alteration reduces protein activity to approximately 30% of wild type activity (Zurflüh, 2008; Shen, 2016). When co-expressed with other disease-causing alleles, residual activity has been reported from 5.2-18% of normal (Danecka, 2015; Shen, 2016). It has been determined that this alteration actually leads to conformational destabilization of the protein and increased degradation while the enzyme function remains intact (Gersting, 2008). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Phenylalanine Hydroxylase Deficiency
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000375565.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
The c.898G>A (p.Ala300Ser) variant is well-documented in the literature and is associated with mild phenylketonuria phenotype that is responsive to BH4 treatment. Across a selection … (more)
The c.898G>A (p.Ala300Ser) variant is well-documented in the literature and is associated with mild phenylketonuria phenotype that is responsive to BH4 treatment. Across a selection of available literature, the p.Ala300Ser variant has been identified in a homozygous state in at least two patients, in a compound heterozygous state in at least 20 patients, and in 40 patients whose zygosity was not explicitly stated but are presumed to be compound heterozygous (Eisensmith et al. 1992; Spaapen et al. 2001; Blau and Erlandsen 2004; Zurflüh et al. 2008; Bercovich et al. 2008; Couce et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00072 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Functional studies showed that the p.Ala300Ser variant did not affect enzyme activity, but resulted in severe misfolding and destabilization of the PAH protein (Gersting et al. 2008). Based on the collective evidence, the p.Ala300Ser variant is classified as pathogenic for phenylalanine hydroxylase deficiency. (less)
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Pathogenic
(May 03, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: yes
Allele origin:
unknown
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV001251825.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
|
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Pathogenic
(Jul 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755232.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
|
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Pathogenic
(Jul 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000239078.9
First in ClinVar: Jul 18, 2015 Last updated: Dec 06, 2016 |
Comment:
Typically associated with either mild hyperphenylalaninemia or mild PKU (Eiken et al., 1996; Danecka et al., 2015; Jeannesson-Thivisol et al., 2015); Published functional studies demonstrate … (more)
Typically associated with either mild hyperphenylalaninemia or mild PKU (Eiken et al., 1996; Danecka et al., 2015; Jeannesson-Thivisol et al., 2015); Published functional studies demonstrate A300S is associated with reduced residual phenylalanine hydroxylase enzyme activity compared to wild-type (Zurfluh et al. 2008; Danecka et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23500595, 26803807, 27682710, 30963030, 18538294, 30667134, 30487145, 25087612, 11486900, 24082139, 17935162, 1301187, 25596310, 23559577, 25750018, 25155776, 27469133, 27121329, 26666653, 28676969, 29431110, 29102225, 30037505, 31355225, 31589614, 33101986) (less)
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Pathogenic
(Sep 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin
Additional submitter:
CUBI - Core Unit Bioinformatics, Berlin Institute of Health
Accession: SCV002574820.1
First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022 |
Sex: male
Tissue: Blood
|
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Pathogenic
(May 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611236.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 31, 2022 |
|
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Pathogenic
(Aug 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
unknown
|
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center
Accession: SCV004030450.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 |
|
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Pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000629225.10
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 300 of the PAH protein (p.Ala300Ser). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 300 of the PAH protein (p.Ala300Ser). This variant is present in population databases (rs5030853, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with PAH deficiency-related diseases (PMID: 22330942, 23764561, 25155776, 25596310, 27682710). ClinVar contains an entry for this variant (Variation ID: 92751). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 15557004, 17935162, 18538294, 25596310, 26803807). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 17, 2024)
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criteria provided, single submitter
Method: research
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804767.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
|
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Pathogenic
(Oct 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249175.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Comment:
PAH: PS3:Very Strong, PM5, PP4:Moderate, PP3
Number of individuals with the variant: 6
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001927245.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
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Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001463134.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740375.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(Apr 01, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Phenylketonuria
Affected status: yes
Allele origin:
germline
|
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Accession: SCV003927833.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
|
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not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
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DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE
Accession: SCV000119761.1
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
|
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not provided
(-)
|
no classification provided
Method: phenotyping only
|
Phenylketonuria
Affected status: yes
Allele origin:
paternal
|
GenomeConnect, ClinGen
Accession: SCV000840271.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more)
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Myopia (present) , Short attention span (present) , Depressivity (present)
Indication for testing: Diagnostic
Age: 10-19 years
Sex: male
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-12-07
Testing laboratory interpretation: Pathogenic
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Co-existence of phenylketonuria either with maple syrup urine disease or Sandhoff disease in two patients from Iran: emphasizing the role of consanguinity. | Abiri M | Journal of pediatric endocrinology & metabolism : JPEM | 2016 | PMID: 27682710 |
Co-expression of phenylalanine hydroxylase variants and effects of interallelic complementation on in vitro enzyme activity and genotype-phenotype correlation. | Shen N | Molecular genetics and metabolism | 2016 | PMID: 26803807 |
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 |
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 complexity of newborn screening follow-up in phenylketonuria. | Hecht LE | JIMD reports | 2014 | PMID: 25155776 |
Molecular genetics of PKU in Poland and potential impact of mutations on BH4 responsiveness. | Bik-Multanowski M | Acta biochimica Polonica | 2013 | PMID: 24350308 |
Mutation analysis in hyperphenylalaninemia patients from South Italy. | Trunzo R | Clinical biochemistry | 2013 | PMID: 23792259 |
Phenylalanine hydroxylase deficiency in the Slovak population: genotype-phenotype correlations and genotype-based predictions of BH4-responsiveness. | Polak E | Gene | 2013 | PMID: 23764561 |
Tetrahydrobiopterin, its mode of action on phenylalanine hydroxylase, and importance of genotypes for pharmacological therapy of phenylketonuria. | Heintz C | Human mutation | 2013 | PMID: 23559577 |
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 |
The spectrum of mutations identified in Cypriot patients with phenylalanine hydroxylase deficiency detected through neonatal screening. | Georgiou T | Clinical biochemistry | 2012 | PMID: 22330942 |
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 |
Significance of genotype in tetrahydrobiopterin-responsive phenylketonuria. | Trefz FK | Journal of inherited metabolic disease | 2009 | PMID: 18956252 |
Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability. | Gersting SW | American journal of human genetics | 2008 | PMID: 18538294 |
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 |
Incidence of BH4-responsiveness in phenylalanine-hydroxylase-deficient Italian patients. | Fiori L | Molecular genetics and metabolism | 2005 | PMID: 16198137 |
Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations. | Erlandsen H | Proceedings of the National Academy of Sciences of the United States of America | 2004 | PMID: 15557004 |
The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. | Blau N | Molecular genetics and metabolism | 2004 | PMID: 15171997 |
Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Dutch neonates. | Spaapen LJ | Journal of inherited metabolic disease | 2001 | PMID: 11486900 |
Mutations of the phenylalanine hydroxylase gene in mild hyperphenylalaninemia: a novel mutation in exon 3. | Zekanowski C | Human mutation | 1997 | PMID: 9298832 |
Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene. | Eisensmith RC | Human mutation | 1992 | PMID: 1301187 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH | - | - | - | - |
http://www.pahdb.mcgill.ca/ | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/1cd06d79-1c2c-4338-936e-15faf0063222 | - | - | - | - |
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Text-mined citations for rs5030853 ...
HelpRecord last updated May 27, 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.