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NM_000277.3(PAH):c.561G>A (p.Trp187Ter)

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Interpretation:
Pathogenic​

Review status:
reviewed by expert panel FDA Recognized Database
Submissions:
11 (Most recent: Sep 30, 2021)
Last evaluated:
Aug 10, 2018
Accession:
VCV000102736.10
Variation ID:
102736
Description:
single nucleotide variant
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NM_000277.3(PAH):c.561G>A (p.Trp187Ter)

Allele ID
108472
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
12q23.2
Genomic location
12: 102855281 (GRCh38) GRCh38 UCSC
12: 103249059 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000012.11:g.103249059C>T
NC_000012.12:g.102855281C>T
NG_008690.2:g.108130G>A
... more HGVS
Protein change
W187*
Other names
NM_000277.2(PAH):c.561G>A
Canonical SPDI
NC_000012.12:102855280:C:T
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00001
Links
ClinGen: CA229624
dbSNP: rs62507336
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 7 reviewed by expert panel Aug 10, 2018 RCV000169529.12
Pathogenic 4 criteria provided, single submitter Dec 27, 2017 RCV000088985.4
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
PAH - - GRCh38
GRCh37
1115 1145

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Aug 10, 2018)
reviewed by expert panel
Method: curation
Phenylketonuria
(Autosomal recessive inheritance)
Allele origin: germline
ClinGen PAH Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV000852146.3
Submitted: (Feb 25, 2019)
Evidence details
Publications
PubMed (1)
Other databases
https://erepo.clinicalgenome.org…
Comment:
PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PM2: Extremely low frequency in gnomAD. MAF=0.00002.; PP4_Moderate: Detected in 3 chromosomes of patients with PAH deficiency. BH4 … (more)
Likely pathogenic
(Jan 06, 2015)
criteria provided, single submitter
Method: literature only
Phenylketonuria
(Autosomal recessive inheritance)
Allele origin: unknown
Counsyl
Accession: SCV000221006.1
Submitted: (Mar 11, 2015)
Evidence details
Publications
PubMed (11)
Pathogenic
(Dec 27, 2017)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000680747.1
Submitted: (Feb 07, 2018)
Evidence details
Comment:
The W187X variant in the PAH gene has been reported in association with phenylalanine hydroxylase deficiency (Liu et al., 2015; Romano et al., 1996) and … (more)
Pathogenic
(Oct 08, 2014)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000744098.1
Submitted: (Apr 17, 2018)
Evidence details
Pathogenic
(Oct 04, 2020)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001442683.1
Submitted: (Nov 10, 2020)
Evidence details
Publications
PubMed (4)
Comment:
Variant summary: PAH c.561G>A (p.Trp187X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Pathogenic
(Jul 30, 2020)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Invitae
Accession: SCV000959031.3
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (4)
Comment:
This sequence change creates a premature translational stop signal (p.Trp187*) in the PAH gene. It is expected to result in an absent or disrupted protein … (more)
Pathogenic
(-)
no assertion criteria provided
Method: clinical testing
Phenylketonuria
Allele origin: germline
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000733125.1
Submitted: (Apr 04, 2018)
Evidence details
Pathogenic
(Sep 16, 2020)
no assertion criteria provided
Method: clinical testing
Phenylketonuria
Allele origin: germline
Natera, Inc.
Accession: SCV001455092.1
Submitted: (Dec 28, 2020)
Evidence details
Pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: germline
Human Genetics - Radboudumc,Radboudumc
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956805.1
Submitted: (Sep 30, 2021)
Evidence details
Pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: germline
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001971621.1
Submitted: (Sep 21, 2021)
Evidence details
not provided
(-)
no assertion provided
Method: not provided
not provided
Allele origin: not provided
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE
Accession: SCV000119589.1
Submitted: (Mar 30, 2012)
Evidence details

Functional evidence

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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 this variant

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Title Author Journal Year Link
Prenatal diagnosis of Chinese families with phenylketonuria. Liu N Genetics and molecular research : GMR 2015 PMID: 26600521
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
Variations in genotype-phenotype correlations in phenylalanine hydroxylase deficiency in Chinese Han population. Zhu T Gene 2013 PMID: 23932990
Chaperone-like therapy with tetrahydrobiopterin in clinical trials for phenylketonuria: is genotype a predictor of response? Sarkissian CN JIMD reports 2012 PMID: 23430918
Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Zurflüh MR Human mutation 2008 PMID: 17935162
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
Molecular epidemiology of phenylalanine hydroxylase deficiency in Southern Italy: a 96% detection rate with ten novel mutations. Daniele A Annals of human genetics 2007 PMID: 17096675
The molecular basis of phenylketonuria in Koreans. Lee DH Journal of human genetics 2004 PMID: 15503242
Mutational spectrum in German patients with phenylalanine hydroxylase deficiency. Aulehla-Scholz C Human mutation 2003 PMID: 12655553
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
Sequence variation at the phenylalanine hydroxylase gene in the British Isles. Tyfield LA American journal of human genetics 1997 PMID: 9012412
PAH deficiency in Italy: correlation of genotype with phenotype in the Sicilian population. Romano V Journal of inherited metabolic disease 1996 PMID: 8830172
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
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c75a3cc6-1a5e-4837-b431-6e2b2a14c0b1 - - - -

Text-mined citations for rs62507336...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 27, 2021