ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.694C>T (p.Gln232Ter)
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
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NM_000277.3(PAH):c.694C>T (p.Gln232Ter)
Variation ID: 102788 Accession: VCV000102788.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q23.2 12: 102855148 (GRCh38) [ NCBI UCSC ] 12: 103248926 (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 Feb 20, 2024 May 31, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000277.3:c.694C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000268.1:p.Gln232Ter nonsense NM_001354304.2:c.694C>T NP_001341233.1:p.Gln232Ter nonsense NC_000012.12:g.102855148G>A NC_000012.11:g.103248926G>A NG_008690.2:g.108263C>T - Protein change
- Q232*
- Other names
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- Canonical SPDI
- NC_000012.12:102855147: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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
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 |
1485 | 1604 |
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 (2) |
criteria provided, single submitter
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May 19, 2017 | RCV000089039.2 | |
Pathogenic (4) |
reviewed by expert panel
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May 31, 2020 | RCV000169464.11 |
Submissions - Germline
Classification
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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
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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
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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
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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
(May 31, 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
Accession: SCV001370877.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
The c.694C>T (p.Gln232Ter) variant in PAH has been reported in multiple individuals with PKU (PP4; PMID: 30050108). This variant has an extremely low allele frequency … (more)
The c.694C>T (p.Gln232Ter) variant in PAH has been reported in multiple individuals with PKU (PP4; PMID: 30050108). This variant has an extremely low allele frequency (MAF=0.00003; PM2). This variant was detected with known pathogenic variant c.442-1G>A (PM3; PMID: 30050108). This is a null variant (nonsense) in exon 6 of 13 (NMD predicted) of PAH, a gene where loss of function is a known mechanism of disease (PVS1). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. (less)
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Pathogenic
(May 19, 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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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601715.2
First in ClinVar: Mar 19, 2014 Last updated: Jan 01, 2022 |
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Pathogenic
(Nov 15, 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: SCV001386850.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln232*) in the PAH gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln232*) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs62507348, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with PAH-related conditions (PMID: 16256386, 23932990, 25087612, 26600521, 27264808, 29390883). 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: 102788). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 10, 2019)
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no assertion criteria provided
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220898.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 23, 2019 |
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Pathogenic
(Sep 11, 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: SCV002088648.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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: SCV000119644.1
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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Analysis of the genotype-phenotype correlation in patients with phenylketonuria in mainland China. | Li N | Scientific reports | 2018 | PMID: 30050108 |
Mutational spectrum of the phenylalanine hydroxylase gene in patients with phenylketonuria in the central region of China. | Zhang Z | Scandinavian journal of clinical and laboratory investigation | 2018 | PMID: 29390883 |
Spectrum of PAH gene variants among a population of Han Chinese patients with phenylketonuria from northern China. | Liu N | BMC medical genetics | 2017 | PMID: 28982351 |
[Genotype and phenotype correlation of phenylalanine hydroxylase deficiency among patients from Henan]. | Zhao D | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2016 | PMID: 27264808 |
Prenatal diagnosis of Chinese families with phenylketonuria. | Liu N | Genetics and molecular research : GMR | 2015 | PMID: 26600521 |
Molecular characterisation of phenylketonuria in a Chinese mainland population using next-generation sequencing. | Li N | Scientific reports | 2015 | PMID: 26503515 |
Characterization of phenylalanine hydroxylase gene mutations in phenylketonuria in Xinjiang of China. | Yu W | International journal of clinical and experimental medicine | 2014 | PMID: 25550961 |
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 |
[Analysis for phenylalanine hydroxylase gene mutations in 35 ethnic Hui children from Ningxia with phenylketonuria]. | Mao X | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2014 | PMID: 24510552 |
Variations in genotype-phenotype correlations in phenylalanine hydroxylase deficiency in Chinese Han population. | Zhu T | Gene | 2013 | PMID: 23932990 |
Phenylketonuria mutations in Northern China. | Song F | Molecular genetics and metabolism | 2005 | PMID: 16256386 |
Molecular characterization of phenylalanine hydroxylase deficiency in Chile. Mutations in brief no. 243. Online. | Pérez B | Human mutation | 1999 | PMID: 10408782 |
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 phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene. | Eisensmith RC | Human mutation | 1992 | PMID: 1301187 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/58217aed-93e8-4080-b19a-9bfa3cd9dea4 | - | - | - | - |
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Text-mined citations for rs62507348 ...
HelpRecord last updated Feb 20, 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.