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NM_000277.3(PAH):c.355C>T (p.Pro119Ser)

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Interpretation:
Likely pathogenic​

Review status:
reviewed by expert panel FDA Recognized Database
Submissions:
6 (Most recent: Jan 7, 2021)
Last evaluated:
Jul 29, 2018
Accession:
VCV000092741.8
Variation ID:
92741
Description:
single nucleotide variant
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NM_000277.3(PAH):c.355C>T (p.Pro119Ser)

Allele ID
98648
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
12q23.2
Genomic location
12: 102877548 (GRCh38) GRCh38 UCSC
12: 103271326 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000012.11:g.103271326G>A
NC_000012.12:g.102877548G>A
NG_008690.2:g.85863C>T
... more HGVS
Protein change
P119S
Other names
NM_000277.2(PAH):c.355C>T
Canonical SPDI
NC_000012.12:102877547:G:A
Functional consequence
-
Global minor allele frequency (GMAF)
0.00020 (A)

Allele frequency
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD), exomes 0.00029
Exome Aggregation Consortium (ExAC) 0.00035
Links
ClinGen: CA220582
dbSNP: rs398123292
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely pathogenic 5 reviewed by expert panel Jul 29, 2018 RCV000178066.11
Likely pathogenic 1 criteria provided, single submitter May 24, 2017 RCV000790751.3
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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
Likely pathogenic
(Jul 29, 2018)
reviewed by expert panel
Method: curation
Phenylketonuria
(Autosomal recessive inheritance)
Allele origin: germline
ClinGen PAH Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV000852139.3
Submitted: (Feb 25, 2019)
Evidence details
Publications
PubMed (2)
Other databases
https://erepo.clinicalgenome.org…
Comment:
PAH-specific ACMG/AMP criteria applied: PP3: in silico analysis supportive of damaging effect; PM3_Strong: In trans with R261Q (PMID 21147011), and in trans with IVS2+1G>A (PMID … (more)
Likely pathogenic
(May 24, 2017)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics
Accession: SCV000230056.5
Submitted: (Jun 30, 2017)
Evidence details
Other databases
http://www.egl-eurofins.com/emvc…
Likely pathogenic
(Feb 22, 2019)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362288.1
Submitted: (Mar 06, 2020)
Evidence details
Publications
PubMed (4)
Comment:
Variant summary: PAH c.355C>T (p.Pro119Ser) results in a non-conservative amino acid change located in the C-terminal domain (IPR019774) of the encoded protein sequence. Five of … (more)
Pathogenic
(Oct 06, 2020)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Invitae
Accession: SCV000827282.4
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (5)
Comment:
This sequence change replaces proline with serine at codon 119 of the PAH protein (p.Pro119Ser). The proline residue is highly conserved and there is a … (more)
Uncertain significance
(Apr 25, 2018)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: unknown
Counsyl
Accession: SCV000800700.1
Submitted: (Jul 10, 2018)
Evidence details
Publications
PubMed (3)
Likely pathogenic
(-)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Baylor Genetics
Accession: SCV001163726.1
Submitted: (Sep 27, 2019)
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
A comprehensive study of phenylalanine hydroxylase gene mutations in the Iranian phenylketonuria patients. Esfahani MS European journal of medical genetics 2019 PMID: 30389586
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
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
Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases. Pey AL American journal of human genetics 2007 PMID: 17924342
The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Blau N Molecular genetics and metabolism 2004 PMID: 15171997
Tetrahydrobiopterin sensitivity in German patients with mild phenylalanine hydroxylase deficiency. Lindner M Human mutation 2003 PMID: 12655554
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH - - - -
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/38a183ee-7e53-4c24-a250-50958f390c78 - - - -

Text-mined citations for rs398123292...

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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 18, 2021