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NM_000277.3(PAH):c.158G>A (p.Arg53His)

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Interpretation:
Uncertain significance​

Review status:
reviewed by expert panel FDA Recognized Database
Submissions:
10 (Most recent: Jun 8, 2021)
Last evaluated:
Aug 10, 2018
Accession:
VCV000102601.9
Variation ID:
102601
Description:
single nucleotide variant
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NM_000277.3(PAH):c.158G>A (p.Arg53His)

Allele ID
108337
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
12q23.2
Genomic location
12: 102912801 (GRCh38) GRCh38 UCSC
12: 103306579 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000012.11:g.103306579C>T
NC_000012.12:g.102912801C>T
NM_000277.3:c.158G>A MANE Select NP_000268.1:p.Arg53His missense
... more HGVS
Protein change
R53H
Other names
NM_000277.2(PAH):c.158G>A
Canonical SPDI
NC_000012.12:102912800:C:T
Functional consequence
-
Global minor allele frequency (GMAF)
0.00300 (T)

Allele frequency
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00062
The Genome Aggregation Database (gnomAD), exomes 0.00168
Trans-Omics for Precision Medicine (TOPMed) 0.00190
The Genome Aggregation Database (gnomAD) 0.00105
1000 Genomes Project 0.00300
Exome Aggregation Consortium (ExAC) 0.00175
Links
ClinGen: CA229447
UniProtKB: P00439#VAR_000878
dbSNP: rs118092776
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 8 reviewed by expert panel Aug 10, 2018 RCV000490373.11
Likely benign 1 criteria provided, single submitter Dec 26, 2019 RCV001175359.1
not provided 1 no assertion provided - RCV000088842.4
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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
1103 1132

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(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: SCV000852170.3
Submitted: (Feb 25, 2019)
Evidence details
Publications
PubMed (1)
Other databases
https://erepo.clinicalgenome.org…
Comment:
PAH-specific ACMG/AMP criteria applied: BS1: MAF=0.01596 in ExAC (138/8648) and 0.0104 in gnomAD (265/18868 with 3 homozygotes); PP4: Detected in a patient with mild hyperphe … (more)
Uncertain significance
(Mar 18, 2016)
criteria provided, single submitter
Method: reference population
Phenylketonuria
Allele origin: germline
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center
Accession: SCV000267433.1
Submitted: (Apr 14, 2016)
Evidence details
Publications
PubMed (1)
Uncertain significance
(May 28, 2019)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: unknown
Mendelics
Accession: SCV001138806.1
Submitted: (Oct 22, 2019)
Evidence details
Likely benign
(Apr 27, 2017)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV001266460.1
Submitted: (Feb 20, 2020)
Evidence details
Publications
PubMed (7)
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
Likely benign
(Dec 26, 2019)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696438.2
Submitted: (Mar 06, 2020)
Evidence details
Publications
PubMed (11)
Comment:
Variant summary: PAH c.158G>A (p.Arg53His) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Five of … (more)
Uncertain significance
(May 18, 2021)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Nilou-Genome Lab
Accession: SCV001716364.1
Submitted: (Jun 08, 2021)
Evidence details
Benign
(Dec 04, 2020)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Invitae
Accession: SCV000754088.4
Submitted: (Jan 07, 2021)
Evidence details
Likely benign
(Jun 07, 2017)
no assertion criteria provided
Method: curation
Phenylketonuria
Allele origin: germline
SingHealth Duke-NUS Institute of Precision Medicine
Accession: SCV000853180.1
Submitted: (Apr 09, 2018)
Evidence details
Benign
(Jan 06, 2020)
no assertion criteria provided
Method: clinical testing
Phenylketonuria
Allele origin: germline
Natera, Inc.
Accession: SCV001455418.1
Submitted: (Dec 28, 2020)
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: SCV000119435.1
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
The molecular epidemiology of hyperphenylalaninemia in Uygur population: incidence from newborn screening and mutational spectra. Su Y Annals of translational medicine 2019 PMID: 31355225
The study of the full spectrum of variants leading to hyperphenylalaninemia have revealed 10 new variants in the PAH gene. Kuznetcova I Metabolic brain disease 2019 PMID: 31332730
Expanded newborn screening for inherited metabolic disorders and genetic characteristics in a southern Chinese population. Lin Y Clinica chimica acta; international journal of clinical chemistry 2019 PMID: 30904546
Estimating carrier frequencies of newborn screening disorders using a whole-genome reference panel of 3552 Japanese individuals. Yamaguchi-Kabata Y Human genetics 2019 PMID: 30887117
Application of Next-Generation Sequencing Following Tandem Mass Spectrometry to Expand Newborn Screening for Inborn Errors of Metabolism: A Multicenter Study. Yang Y Frontiers in genetics 2019 PMID: 30838026
Mutation spectrum of PAH gene in phenylketonuria patients in Northwest China: identification of twenty novel variants. Yan Y Metabolic brain disease 2019 PMID: 30747360
Three novel variants (p.Glu178Lys, p.Val245Met, p.Ser250Phe) of the phenylalanine hydroxylase (PAH) gene impair protein expression and function in vitro. Zong Y Gene 2018 PMID: 29653233
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
Correlation between genotype and the tetrahydrobiopterin-responsive phenotype in Chinese patients with phenylketonuria. Tao J Pediatric research 2015 PMID: 26322415
The mutation spectrum of the phenylalanine hydroxylase (PAH) gene and associated haplotypes reveal ethnic heterogeneity in the Taiwanese population. Liang Y Journal of human genetics 2014 PMID: 24401910
Mutational spectrum of phenylketonuria in the Chinese Han population: a novel insight into the geographic distribution of the common mutations. Zhu T Pediatric research 2010 PMID: 19915519
A mutation analysis of the phenylalanine hydroxylase (PAH) gene in the Israeli population. Bercovich D Annals of human genetics 2008 PMID: 18294361
Structural and functional analyses of mutations of the human phenylalanine hydroxylase gene. Kim SW Clinica chimica acta; international journal of clinical chemistry 2006 PMID: 16253218
Phenylketonuria mutations in Northern China. Song F Molecular genetics and metabolism 2005 PMID: 16256386
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
Identification of three novel mutations in Korean phenylketonuria patients: R53H, N207D, and Y325X. Park YS Human mutation 1998 PMID: 9452061
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/0b0aa28d-6844-4b34-a270-410f26ce9504 - - - -

Text-mined citations for rs118092776...

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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 Aug 27, 2021