Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation

ClinVar Genomic variation as it relates to human health

Advanced search

NM_000277.3(PAH):c.805A>C (p.Ile269Leu)

Help
Interpretation:
Pathogenic​

Review status:
reviewed by expert panel FDA Recognized Database
Submissions:
11 (Most recent: Nov 19, 2021)
Last evaluated:
Dec 10, 2018
Accession:
VCV000102842.14
Variation ID:
102842
Description:
single nucleotide variant
Help

NM_000277.3(PAH):c.805A>C (p.Ile269Leu)

Allele ID
108578
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
12q23.2
Genomic location
12: 102852852 (GRCh38) GRCh38 UCSC
12: 103246630 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000012.11:g.103246630T>G
NC_000012.12:g.102852852T>G
NG_008690.2:g.110559A>C
... more HGVS
Protein change
I269L
Other names
NM_000277.1(PAH):c.805A>C
Canonical SPDI
NC_000012.12:102852851:T:G
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.00013
Links
ClinGen: CA229775
UniProtKB: P00439#VAR_000969
dbSNP: rs62508692
VarSome
Help

Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 8 reviewed by expert panel Dec 10, 2018 RCV000281383.15
Pathogenic 3 criteria provided, multiple submitters, no conflicts May 5, 2021 RCV000089101.4
Help
Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
PAH - - GRCh38
GRCh37
1115 1145

Submitted interpretations and evidence

Help
Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Dec 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: SCV000886598.1
Submitted: (Feb 25, 2019)
Evidence details
Publications
PubMed (4)
Other databases
https://erepo.clinicalgenome.org…
Comment:
The c.805A>C (p.Ile269Leu) variant in PAH has been reported in multiple individuals with PAH deficiency, including non-PKU HPA (BH4 deficiency excluded). (PP4_Moderate; PMID10767174, PMID 2350059). … (more)
Pathogenic
(Jun 12, 2015)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics
Accession: SCV000330984.4
Submitted: (Sep 19, 2018)
Evidence details
Publications
PubMed (2)
Other databases
http://www.egl-eurofins.com/emvc…
http://www.pahdb.mcgill.ca/
Likely pathogenic
(Nov 02, 2018)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV000915570.1
Submitted: (Feb 01, 2019)
Evidence details
Publications
PubMed (3)
Comment:
The PAH c.805A>C (p.Ile269Leu) variant has been reported in three studies in which it is found in a total of five individuals, including one sibling … (more)
Pathogenic
(Jul 20, 2020)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362291.2
Submitted: (Aug 06, 2020)
Evidence details
Publications
PubMed (5)
Comment:
Variant summary: PAH c.805A>C (p.Ile269Leu) results in a conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain of the encoded protein … (more)
Pathogenic
(Aug 26, 2020)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Invitae
Accession: SCV000827700.4
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (5)
Comment:
This sequence change replaces isoleucine with leucine at codon 269 of the PAH protein (p.Ile269Leu). The isoleucine residue is highly conserved and there is a … (more)
Pathogenic
(May 05, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV001784251.1
Submitted: (Aug 13, 2021)
Evidence details
Comment:
Classified as responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh et al., 2008); This variant is associated with the following publications: (PMID: 32668217, 9521426, 27121329, 17935162, 14726806, … (more)
Uncertain significance
(Jan 16, 2019)
no assertion criteria provided
Method: clinical testing
Phenylketonuria
Allele origin: unknown
Counsyl
Accession: SCV000800539.2
Submitted: (Aug 05, 2019)
Evidence details
Publications
PubMed (8)
Likely pathogenic
(Apr 01, 2020)
no assertion criteria provided
Method: clinical testing
Phenylketonuria
Allele origin: germline
Elsea Laboratory,Baylor College of Medicine
Accession: SCV001424211.1
Submitted: (Apr 07, 2020)
Evidence details
Pathogenic
(Sep 16, 2020)
no assertion criteria provided
Method: clinical testing
Phenylketonuria
Allele origin: germline
Natera, Inc.
Accession: SCV001453104.1
Submitted: (Dec 28, 2020)
Evidence details
Pathogenic
(Nov 02, 2021)
no assertion criteria provided
Method: clinical testing
Phenylketonuria
Allele origin: germline
PerkinElmer Genomics
Accession: SCV002016489.1
Submitted: (Nov 19, 2021)
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: SCV000119708.1
Submitted: (Mar 30, 2012)
Evidence details

Functional evidence

Help
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

Help
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
Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria. Aldámiz-Echevarría L Journal of human genetics 2016 PMID: 27121329
Accurate molecular diagnosis of phenylketonuria and tetrahydrobiopterin-deficient hyperphenylalaninemias using high-throughput targeted sequencing. Trujillano D European journal of human genetics : EJHG 2014 PMID: 23942198
Molecular genetics of PKU in Poland and potential impact of mutations on BH4 responsiveness. Bik-Multanowski M Acta biochimica Polonica 2013 PMID: 24350308
Molecular epidemiology and BH4-responsiveness in patients with phenylalanine hydroxylase deficiency from Galicia region of Spain. Couce ML Gene 2013 PMID: 23500595
Hyperphenylalaninemia in the Czech Republic: genotype-phenotype correlations and in silico analysis of novel missense mutations. Réblová K Clinica chimica acta; international journal of clinical chemistry 2013 PMID: 23357515
Phenylalanine hydroxylase deficiency: molecular epidemiology and predictable BH4-responsiveness in South Portugal PKU patients. Rivera I Molecular genetics and metabolism 2011 PMID: 21871829
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
Response of phenylketonuria to tetrahydrobiopterin. Michals-Matalon K The Journal of nutrition 2007 PMID: 17513426
Biopterin responsive phenylalanine hydroxylase deficiency. Matalon R Genetics in medicine : official journal of the American College of Medical Genetics 2004 PMID: 14726806
The correlation of genotype and phenotype in Portuguese hyperphenylalaninemic patients. Rivera I Molecular genetics and metabolism 2000 PMID: 10767174
Eight new mutations of the phenylalanine hydroxylase gene in Italian patients with hyperphenylalaninemia. Bosco P Human mutation 1998 PMID: 9521426
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH - - - -
http://www.pahdb.mcgill.ca/ - - - -
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/980fb510-b83f-4177-95ab-dc11302d825a - - - -

Text-mined citations for rs62508692...

Help
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 Nov 28, 2021