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NM_000277.3(PAH):c.1A>G (p.Met1Val)

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Interpretation:
Pathogenic​

Review status:
reviewed by expert panel FDA Recognized Database
Submissions:
10 (Most recent: Sep 1, 2021)
Last evaluated:
Aug 7, 2018
Accession:
VCV000000586.6
Variation ID:
586
Description:
single nucleotide variant
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NM_000277.3(PAH):c.1A>G (p.Met1Val)

Allele ID
15625
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
12q23.2
Genomic location
12: 102917130 (GRCh38) GRCh38 UCSC
12: 103310908 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000012.11:g.103310908T>C
NC_000012.12:g.102917130T>C
NG_008690.2:g.46281A>G
... more HGVS
Protein change
M1V
Other names
NM_000277.2(PAH):c.1A>G
Canonical SPDI
NC_000012.12:102917129:T:C
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Links
ClinGen: CA114360
OMIM: 612349.0009
dbSNP: rs62514891
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 6 reviewed by expert panel Aug 7, 2018 RCV000000616.16
Pathogenic 3 criteria provided, single submitter Sep 29, 2015 RCV000088868.3
Pathogenic 1 no assertion criteria provided Jul 1, 1992 RCV000000617.5
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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
1091 1120

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Aug 07, 2018)
reviewed by expert panel
Method: curation
Phenylketonuria
(Autosomal recessive inheritance)
Allele origin: germline
ClinGen PAH Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV000852133.3
Submitted: (Feb 25, 2019)
Evidence details
Publications
PubMed (2)
Other databases
https://erepo.clinicalgenome.org…
Comment:
PAH-specific ACMG/AMP criteria applied: PVS1: Initiation codon variant; PM2: gnomAD MAF=0.00002; PP4_Moderate: Seen in PKU patients. BH4 disorders ruled out. (PMID:2574002); PS3: <3% (PMID:9450897). In … (more)
Likely pathogenic
(Dec 17, 2014)
criteria provided, single submitter
Method: literature only
Phenylketonuria
(Autosomal recessive inheritance)
Allele origin: unknown
Counsyl
Accession: SCV000220962.1
Submitted: (Mar 11, 2015)
Evidence details
Publications
PubMed (6)
Pathogenic
(Apr 24, 2017)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696442.1
Submitted: (Jan 25, 2018)
Evidence details
Publications
PubMed (3)
Comment:
Variant summary: The PAH c.1A>G (p.Met1Val) variant involves the alteration of a conserved nucleotide at the translation start site and 3/4 in silico tools predict … (more)
Pathogenic
(Sep 29, 2015)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics
Accession: SCV000331821.4
Submitted: (Sep 19, 2018)
Evidence details
Other databases
http://www.egl-eurofins.com/emvc…
http://www.pahdb.mcgill.ca/
Pathogenic
(Jul 09, 2020)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Invitae
Accession: SCV001215549.2
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (5)
Comment:
This sequence change affects the initiator methionine of the PAH mRNA. The next in-frame methionine is located at codon 180. This variant is present in … (more)
Pathogenic
(Jul 01, 1992)
no assertion criteria provided
Method: literature only
HYPERPHENYLALANINEMIA, NON-PKU
Allele origin: germline
OMIM
Accession: SCV000020767.4
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (3)
Pathogenic
(Sep 16, 2020)
no assertion criteria provided
Method: clinical testing
Phenylketonuria
Allele origin: germline
Natera, Inc.
Accession: SCV001459233.1
Submitted: (Dec 28, 2020)
Evidence details
Pathogenic
(Jan 06, 2020)
no assertion criteria provided
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV001820869.1
Submitted: (Sep 01, 2021)
Evidence details
Comment:
Seen in a patient with classic PKU in the presence of a second pathogenic variant in PAH and BH4 responsiveness was unknown (Jeannesson-Thivisol et al., … (more)
Pathogenic
(Jul 01, 1992)
no assertion criteria provided
Method: literature only
PHENYLKETONURIA
Allele origin: germline
OMIM
Accession: SCV000020766.4
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (3)
not provided
(-)
no assertion provided
Method: not provided
not provided
Allele origin: not provided
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE
Accession: SCV000119464.1
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
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
Phenylalanine hydroxylase deficiency in Mexico: genotype-phenotype correlations, BH4 responsiveness and evidence of a founder effect. Vela-Amieva M Clinical genetics 2015 PMID: 24941924
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
Mutation at the phenylalanine hydroxylase gene (PAH) and its use to document population genetic variation: the Quebec experience. Carter KC European journal of human genetics : EJHG 1998 PMID: 9781015
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
In vitro expression analysis of mutations in phenylalanine hydroxylase: linking genotype to phenotype and structure to function. Waters PJ Human mutation 1998 PMID: 9450897
Time and space clusters of the French-Canadian M1V phenylketonuria mutation in France. Lyonnet S American journal of human genetics 1992 PMID: 1609797
In vitro and in vivo correlations for I65T and M1V mutations at the phenylalanine hydroxylase locus. John SW Human mutation 1992 PMID: 1301201
Five mutations at the PAH locus account for almost 90% of PKU mutations in French-Canadians from eastern Quebec. John SW Human mutation 1992 PMID: 1301193
Novel PKU mutation on haplotype 2 in French-Canadians. John SW American journal of human genetics 1989 PMID: 2574002
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH - - - -
http://www.pahdb.mcgill.ca/ - - - -
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/89f04437-ed5d-4735-8c4a-a9b1d91d10ea - - - -

Text-mined citations for rs62514891...

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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 07, 2021