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NM_000277.3(PAH):c.204A>T (p.Arg68Ser)

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Interpretation:
Pathogenic​

Review status:
reviewed by expert panel FDA Recognized Database
Submissions:
9 (Most recent: Jul 4, 2021)
Last evaluated:
Jul 24, 2020
Accession:
VCV000092738.10
Variation ID:
92738
Description:
single nucleotide variant
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NM_000277.3(PAH):c.204A>T (p.Arg68Ser)

Allele ID
98645
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
12q23.2
Genomic location
12: 102894883 (GRCh38) GRCh38 UCSC
12: 103288661 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000012.11:g.103288661T>A
NC_000012.12:g.102894883T>A
NG_008690.2:g.68528A>T
... more HGVS
Protein change
R68S
Other names
-
Canonical SPDI
NC_000012.12:102894882:T:A
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Exome Aggregation Consortium (ExAC) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00005
Links
ClinGen: CA273113
UniProtKB: P00439#VAR_000885
dbSNP: rs76394784
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 5 reviewed by expert panel Jul 24, 2020 RCV000150091.14
Pathogenic 4 criteria provided, multiple submitters, no conflicts Oct 1, 2019 RCV000078517.8
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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
1084 1112

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Jul 24, 2020)
reviewed by expert panel
Method: curation
Phenylketonuria
(Autosomal recessive inheritance)
Allele origin: germline
ClinGen PAH Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV001448287.1
Submitted: (Dec 03, 2020)
Evidence details
Publications
PubMed (2)
Other databases
https://erepo.clinicalgenome.org…
Comment:
The c.204A>T (p.Arg68Ser) variant in PAH was reported in a Spanish patient with mild/moderate PKU. A defect in the synthesis or regeneration pathways 6R-BH4 was … (more)
Pathogenic
(Aug 12, 2016)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888347.1
Submitted: (Aug 31, 2018)
Evidence details
Pathogenic
(Oct 01, 2019)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
CeGaT Praxis fuer Humangenetik Tuebingen
Accession: SCV001250397.5
Submitted: (Jul 04, 2021)
Evidence details
Likely pathogenic
(Aug 26, 2014)
criteria provided, single submitter
Method: literature only
Phenylketonuria
(Autosomal recessive inheritance)
Allele origin: unknown
Counsyl
Accession: SCV000220635.1
Submitted: (Mar 11, 2015)
Evidence details
Publications
PubMed (21)
Pathogenic
(Sep 09, 2016)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696443.1
Submitted: (Jan 25, 2018)
Evidence details
Publications
PubMed (3)
Comment:
Variant summary: The PAH c.204A>T (p.Arg68Ser) variant causes a missense change involving a non-conserved nucleotide with 5/5 in silico tools predicting a damaging outcome. The … (more)
Pathogenic
(Nov 13, 2017)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics
Accession: SCV000110373.8
Submitted: (Sep 19, 2018)
Evidence details
Publications
PubMed (2)
Other databases
http://www.egl-eurofins.com/emvc…
Pathogenic
(Oct 30, 2020)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Invitae
Accession: SCV000629187.5
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (7)
Comment:
This sequence change replaces arginine with serine at codon 68 of the PAH protein (p.Arg68Ser). The arginine residue is highly conserved and there is a … (more)
Pathogenic
(Sep 16, 2020)
no assertion criteria provided
Method: clinical testing
Phenylketonuria
Allele origin: germline
Natera, Inc.
Accession: SCV001455115.1
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: SCV000119467.1
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
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
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
Molecular genetics of PKU in Poland and potential impact of mutations on BH4 responsiveness. Bik-Multanowski M Acta biochimica Polonica 2013 PMID: 24350308
Phenylalanine hydroxylase deficiency in the Slovak population: genotype-phenotype correlations and genotype-based predictions of BH4-responsiveness. Polak E Gene 2013 PMID: 23764561
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
Chaperone-like therapy with tetrahydrobiopterin in clinical trials for phenylketonuria: is genotype a predictor of response? Sarkissian CN JIMD reports 2012 PMID: 23430918
[Mutation analysis of the phenylalanine hydroxylase gene of phenylketonuria patients of Kemerovskaya Oblast' and Saha Republic]. Baturina OA TSitologiia i genetika 2012 PMID: 23074961
Utility of phenylalanine hydroxylase genotype for tetrahydrobiopterin responsiveness classification in patients with phenylketonuria. Quirk ME Molecular genetics and metabolism 2012 PMID: 22841515
Protein stability and in vivo concentration of missense mutations in phenylalanine hydroxylase. Shi Z Proteins 2012 PMID: 21953985
Phenylalanine hydroxylase deficiency: molecular epidemiology and predictable BH4-responsiveness in South Portugal PKU patients. Rivera I Molecular genetics and metabolism 2011 PMID: 21871829
Metabolic phenotypes of phenylketonuria. Kinetic and molecular evaluation of the Blaskovics protein loading test. Langenbeck U Journal of inherited metabolic disease 2009 PMID: 19609714
Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Zurflüh MR Human mutation 2008 PMID: 17935162
Response of phenylketonuria to tetrahydrobiopterin. Michals-Matalon K The Journal of nutrition 2007 PMID: 17513426
Response of patients with phenylketonuria in the US to tetrahydrobiopterin. Matalon R Molecular genetics and metabolism 2005 PMID: 16143554
Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations. Erlandsen H Proceedings of the National Academy of Sciences of the United States of America 2004 PMID: 15557004
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
Mutational spectrum in German patients with phenylalanine hydroxylase deficiency. Aulehla-Scholz C Human mutation 2003 PMID: 12655553
Should newborn mutation scanning for hyperphenylalaninaemia and galactosaemia be implemented? A Polish experience. Zekanowski C Journal of medical screening 2001 PMID: 11678552
Molecular basis of phenylketonuria in Cuba. Desviat LR Human mutation 2001 PMID: 11524738
Missense mutations in the N-terminal domain of human phenylalanine hydroxylase interfere with binding of regulatory phenylalanine. Gjetting T American journal of human genetics 2001 PMID: 11326337
In vitro expression analysis of R68G and R68S mutations in phenylalanine hydroxylase gene. Zekanowsk C Acta biochimica Polonica 2000 PMID: 11051201
Should genetic analysis in newborn screening and a heterozygote test for hyperphenylalaninaemia be recommended? An Italian study. Rottoli A Journal of medical screening 1999 PMID: 10693064
Mutations in exon 3 of the PAH gene causing mild hyperphenylalaninemia. Zekanowski C Genetic testing 1999 PMID: 10495930
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
Phenylalanine hydroxylase deficiency in a population in Germany: mutational profile and nine novel mutations. Guldberg P Human mutation 1996 PMID: 8889590
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 - - - -
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6b7ec948-f2f5-4aeb-8fae-b588b8369c3d - - - -

Text-mined citations for rs76394784...

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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 Sep 12, 2021