ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.526C>T (p.Arg176Ter)
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.526C>T (p.Arg176Ter)
Variation ID: 102723 Accession: VCV000102723.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q23.2 12: 102855316 (GRCh38) [ NCBI UCSC ] 12: 103249094 (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 Aug 13, 2018 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000277.3:c.526C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000268.1:p.Arg176Ter nonsense NM_001354304.2:c.526C>T NP_001341233.1:p.Arg176Ter nonsense NC_000012.12:g.102855316G>A NC_000012.11:g.103249094G>A NG_008690.2:g.108095C>T - Protein change
- R176*
- Other names
- NM_000277.2(PAH):c.526C>T
- Canonical SPDI
- NC_000012.12:102855315: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.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00004
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
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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
Help
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
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
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Jul 20, 2018 | RCV000088971.9 | |
Pathogenic (11) |
reviewed by expert panel
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Aug 13, 2018 | RCV000179282.17 |
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 13, 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
Accession: SCV000852175.4
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
Comment:
PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PM2: ExAC MAF: 0.00010; PP4_Moderate: BH4 defect excluded in all patients in Liu 2015. Identified in 6 patients … (more)
PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PM2: ExAC MAF: 0.00010; PP4_Moderate: BH4 defect excluded in all patients in Liu 2015. Identified in 6 patients in this study (PMID:10394930; PMID:26600521); PM3_Strong: Identified in 6 patients, in trans with R243Q and R241C (both pathogenic) (PMID:26600521). 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: (PVS1, PM2, PP4_Moderate, PM3_Strong). (less)
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Pathogenic
(Mar 03, 2016)
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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: SCV000696453.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
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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
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000744099.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
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Pathogenic
(Jul 26, 2016)
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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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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745573.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
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Pathogenic
(Aug 08, 2014)
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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: SCV000231507.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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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: SCV000893951.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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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: SCV001810542.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Pathogenic
(Jul 20, 2018)
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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: SCV000888349.2
First in ClinVar: Dec 15, 2018 Last updated: Jan 01, 2022 |
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Pathogenic
(Sep 01, 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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3billion
Accession: SCV002573258.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Stop-gained (nonsense) is predicted to result in … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 26600521). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000102723 / PMID: 8268925). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Global developmental delay (present) , Motor delay (present) , Delayed speech and language development (present) , Cognitive impairment (present)
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Pathogenic
(Oct 05, 2023)
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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: SCV004201383.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 18, 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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Invitae
Accession: SCV000629197.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg176*) 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.Arg176*) 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 (rs199475575, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with phenyketonuria (PMID: 8268925, 17935162, 23514811, 26413448, 26503515). ClinVar contains an entry for this variant (Variation ID: 102723). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 21, 2016)
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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: SCV000485295.2
First in ClinVar: Jun 28, 2015 Last updated: Apr 22, 2019 |
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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: SCV001455097.1
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: SCV000119574.1
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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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 |
Mutations of the phenylalanine hydroxylase gene in Iranian patients with phenylketonuria. | Biglari A | SpringerPlus | 2015 | PMID: 26413448 |
Correlation between genotype and the tetrahydrobiopterin-responsive phenotype in Chinese patients with phenylketonuria. | Tao J | Pediatric research | 2015 | PMID: 26322415 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
A preliminary mutation analysis of phenylketonuria in southwest Iran. | Ajami N | Genetics and molecular research : GMR | 2013 | PMID: 24301756 |
Molecular epidemiology and genotype-phenotype correlation in phenylketonuria patients from South Spain. | Bueno MA | Journal of human genetics | 2013 | PMID: 23514811 |
Molecular epidemiology and BH4-responsiveness in patients with phenylalanine hydroxylase deficiency from Galicia region of Spain. | Couce ML | Gene | 2013 | PMID: 23500595 |
Molecular analysis of exons 6 and 7 of phenylalanine hydroxylase gene mutations in Phenylketonuria patients in Western Iran. | Moradi K | Indian journal of human genetics | 2012 | PMID: 23716935 |
Mutation spectrum of the PAH gene in the PKU patients from Khorasan Razavi province of Iran. | Hamzehloei T | Gene | 2012 | PMID: 22763404 |
Phenylalanine hydroxylase deficiency: molecular epidemiology and predictable BH4-responsiveness in South Portugal PKU patients. | Rivera I | Molecular genetics and metabolism | 2011 | PMID: 21871829 |
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 |
Mutation spectrum of phenylketonuria in Iranian population. | Zare-Karizi Sh | Molecular genetics and metabolism | 2011 | PMID: 20920871 |
Mutation analysis of phenylketonuria patients from Morocco: high prevalence of mutation G352fsdelG and detection of a novel mutation p.K85X. | Dahri S | Clinical biochemistry | 2010 | PMID: 19786003 |
Mutation characteristics of the PAH gene in four nationality groups in Xinjiang of China. | Yu WZ | Journal of genetics | 2008 | PMID: 19147918 |
PKU in Minas Gerais State, Brazil: mutation analysis. | Santos LL | Annals of human genetics | 2008 | PMID: 18798839 |
Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. | Zurflüh MR | Human mutation | 2008 | PMID: 17935162 |
The molecular basis of phenylketonuria in Koreans. | Lee DH | Journal of human genetics | 2004 | PMID: 15503242 |
Tetrahydrobiopterin responsiveness: results of the BH4 loading test in 31 Spanish PKU patients and correlation with their genotype. | Desviat LR | Molecular genetics and metabolism | 2004 | PMID: 15464430 |
A hypothesis on the biochemical mechanism of BH(4)-responsiveness in phenylalanine hydroxylase deficiency. | Steinfeld R | Amino acids | 2003 | PMID: 12836060 |
Mutational spectrum in German patients with phenylalanine hydroxylase deficiency. | Aulehla-Scholz C | Human mutation | 2003 | PMID: 12655553 |
The molecular basis of phenylketonuria in Lithuania. | Kasnauskiene J | Human mutation | 2003 | PMID: 12655550 |
Molecular basis of phenylketonuria in Cuba. | Desviat LR | Human mutation | 2001 | PMID: 11524738 |
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 |
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 |
Mutational spectrum of phenylalanine hydroxylase deficiency in Sicily: implications for diagnosis of hyperphenylalaninemia in southern Europe. | Guldberg P | Human molecular genetics | 1993 | PMID: 8268925 |
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/08d51386-af9e-4de1-8e7b-0dc6c2252c91 | - | - | - | - |
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Text-mined citations for rs199475575 ...
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.