ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.1033G>T (p.Ala345Ser)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000277.3(PAH):c.1033G>T (p.Ala345Ser)
Variation ID: 102484 Accession: VCV000102484.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q23.2 12: 102844368 (GRCh38) [ NCBI UCSC ] 12: 103238146 (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 Jun 17, 2024 Jun 5, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000277.3:c.1033G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000268.1:p.Ala345Ser missense NM_001354304.2:c.1033G>T NP_001341233.1:p.Ala345Ser missense NC_000012.12:g.102844368C>A NC_000012.11:g.103238146C>A NG_008690.2:g.119043G>T P00439:p.Ala345Ser - Protein change
- A345S
- Other names
- p.A345S:GCT>TCT
- Canonical SPDI
- NC_000012.12:102844367: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
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PAH | - | - |
GRCh38 GRCh37 |
1496 | 1616 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 21, 2022 | RCV000088715.9 | |
Pathogenic (7) |
reviewed by expert panel
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Jun 5, 2020 | RCV000586982.12 |
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
(Jun 05, 2020)
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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: SCV001762344.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
Comment:
The c.1033G>T (p.Ala345Ser) variant in PAH has been reported in multiple individuals with PAH deficiency. (PMID: 24368688, 17502162, 3430918). This variant has an extremely low … (more)
The c.1033G>T (p.Ala345Ser) variant in PAH has been reported in multiple individuals with PAH deficiency. (PMID: 24368688, 17502162, 3430918). This variant has an extremely low allele frequency (MAF=0.00008) in gnomAD. It was detected with multiple pathogenic variants: p.R408W (in trans, PMID: 24368688); c.1045T>C, c.194T>C (PMID: 17502162); p.F39del, c.47_48delCT (aka c.43_44CT), c.1066-11G>A (PMID: 23430918); p.E280K, p.L348V, p.Y414C (PMID: 31623983). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_VS, PM2, PP3, PP4. (less)
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Pathogenic
(Mar 30, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696422.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The PAH c.1033G>T (p.Ala345Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within the C-terminal … (more)
Variant summary: The PAH c.1033G>T (p.Ala345Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within the C-terminal aromatic amino acid hydroxylase domain (InterPro) and 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.0000166 (2/120330 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). Published studies have identified the variant in numerous with patients with PKU and/or HPA, including reports of this variant in compound heterozygosity with other pathogenic/likely pathogenic variants and evidence that the variant cosegregates with disease in a family (Ho_JIMDReports_2013). Additionally, one publication that analyzed the crystal structure of PAH protein reported that the variant of interest is one of "three residues in the active site that are located near the (putative) location of substrate binding or in the region near the catalytic iron" sites, suggesting the variant likely disrupts the critical functions of the protein (Erlandsen_Pediatrics_2003). There are no published in vitro functional studies for the variant; however calculation of the energetic impact (G) by structural modeling shows that this variant leads to lower impact on PAH stability and predicted to cause mild hyperphenylalaninemia (Pey_2007). 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
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893269.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004209569.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Dec 04, 2014)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000281653.2
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
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Likely pathogenic
(Jan 17, 2017)
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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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Counsyl
Accession: SCV000789292.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
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Pathogenic
(May 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000239081.15
First in ClinVar: Jul 18, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Responsive to tetrahydrobiopterin (BH4) therapy is unclear (Sarkissian et al., 2012); This variant is associated with the following publications: (PMID: 24368688, 25525159, 14654665, 23430918, 3430918, 17502162, 31623983, 27535533, 32778825, 32668217) (less)
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Pathogenic
(Oct 21, 2022)
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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: SCV004222237.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.000023 (3/129068 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more)
The frequency of this variant in the general population, 0.000023 (3/129068 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant is associated with a variable phenotype that ranges from non-PKU hyperphenylalaninemia to classic PKU (PMIDs: 32668217 (2020), 24368688 (2014), 23430918 (2012), 17502162 (2007), and 12173030 (2002)). In addition, this variant has been observed in individuals with reported PAH deficiency (PMID: 24368688 (2014) and 17502162 (2007)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Nov 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001235796.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 345 of the PAH protein (p.Ala345Ser). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 345 of the PAH protein (p.Ala345Ser). This variant is present in population databases (rs62516062, gnomAD 0.008%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 17502162, 23430918, 24368688). 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: 102484). 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%. For these reasons, this variant has been classified as Pathogenic. (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
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Natera, Inc.
Accession: SCV001463125.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE
Accession: SCV000119295.1
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The role of exome sequencing in newborn screening for inborn errors of metabolism. | Adhikari AN | Nature medicine | 2020 | PMID: 32778825 |
The Genetic Landscape and Epidemiology of Phenylketonuria. | Hillert A | American journal of human genetics | 2020 | PMID: 32668217 |
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 |
Chaperone-like therapy with tetrahydrobiopterin in clinical trials for phenylketonuria: is genotype a predictor of response? | Sarkissian CN | JIMD reports | 2012 | PMID: 23430918 |
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 |
Mutations in the phenylalanine hydroxylase gene identified in 95 patients with phenylketonuria using novel systems of mutation scanning and specific genotyping based upon thermal melt profiles. | Dobrowolski SF | Molecular genetics and metabolism | 2007 | PMID: 17502162 |
Structural studies on phenylalanine hydroxylase and implications toward understanding and treating phenylketonuria. | Erlandsen H | Pediatrics | 2003 | PMID: 14654665 |
Phenylketonuria in a low incidence population: molecular characterisation of mutations in Finland. | Guldberg P | Journal of medical genetics | 1995 | PMID: 8825928 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/9bd06960-5c2f-4ce6-a141-0f0702afd6cf | - | - | - | - |
Text-mined citations for rs62516062 ...
HelpRecord last updated Jun 17, 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.