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NM_000277.3(PAH):c.1184C>G (p.Ala395Gly)

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Interpretation:
Pathogenic/Likely pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
5 (Most recent: Jan 7, 2021)
Last evaluated:
Oct 27, 2020
Accession:
VCV000102549.4
Variation ID:
102549
Description:
single nucleotide variant
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NM_000277.3(PAH):c.1184C>G (p.Ala395Gly)

Allele ID
108285
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
12q23.2
Genomic location
12: 102843661 (GRCh38) GRCh38 UCSC
12: 103237439 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000012.11:g.103237439G>C
NC_000012.12:g.102843661G>C
NM_000277.3:c.1184C>G MANE Select NP_000268.1:p.Ala395Gly missense
... more HGVS
Protein change
A395G
Other names
-
Canonical SPDI
NC_000012.12:102843660:G:C
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00003
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00000
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Links
ClinGen: CA286498
UniProtKB: P00439#VAR_001030
dbSNP: rs62508736
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic/Likely pathogenic 4 criteria provided, multiple submitters, no conflicts Oct 27, 2020 RCV000410586.5
not provided 1 no assertion provided - RCV000088783.3
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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 18, 2016)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: unknown
Counsyl
Accession: SCV000485283.1
Submitted: (Nov 23, 2016)
Evidence details
Pathogenic
(Nov 16, 2018)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917929.1
Submitted: (Apr 24, 2019)
Evidence details
Publications
PubMed (2)
Comment:
Variant summary: PAH c.1184C>G (p.Ala395Gly) results in a non-conservative amino acid change located in the C-terminal domain, containing the catalytic domain and the coiled-coil C-terminal … (more)
Pathogenic
(Oct 27, 2020)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Invitae
Accession: SCV001220571.2
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (8)
Comment:
This sequence change replaces alanine with glycine at codon 395 of the PAH protein (p.Ala395Gly). The alanine residue is highly conserved and there is a … (more)
Likely pathogenic
(Apr 28, 2016)
no assertion criteria provided
Method: research
Phenylketonuria
Allele origin: paternal
Division of Human Genetics,Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536786.1
Submitted: (Jan 23, 2017)
Evidence details
Publications
PubMed (1)
not provided
(-)
no assertion provided
Method: not provided
not provided
Allele origin: not provided
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE
Accession: SCV000119370.1
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
Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria. Aldámiz-Echevarría L Journal of human genetics 2016 PMID: 27121329
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
Utility of phenylalanine hydroxylase genotype for tetrahydrobiopterin responsiveness classification in patients with phenylketonuria. Quirk ME Molecular genetics and metabolism 2012 PMID: 22841515
Genotype-phenotype correlations analysis of mutations in the phenylalanine hydroxylase (PAH) gene. Bercovich D Journal of human genetics 2008 PMID: 18299955
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
Phenylketonuria mutations in Northern China. Song F Molecular genetics and metabolism 2005 PMID: 16256386
Tetrahydrobiopterin responsiveness in phenylketonuria. Two new cases and a review of molecular genetic findings. Lässker U Journal of inherited metabolic disease 2002 PMID: 11999982
In vitro expression of 34 naturally occurring mutant variants of phenylalanine hydroxylase: correlation with metabolic phenotypes and susceptibility toward protein aggregation. Gjetting T Molecular genetics and metabolism 2001 PMID: 11161839
Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency: report from the Maternal Phenylketonuria Collaborative Study. Güttler F Pediatrics 1999 PMID: 10429004
Characterization of phenylalanine hydroxylase alleles in untreated phenylketonuria patients from Victoria, Australia: origin of alleles and haplotypes. Ramus SJ American journal of human genetics 1995 PMID: 7726156

Text-mined citations for rs62508736...

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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 Jun 14, 2021