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NM_000277.3(PAH):c.1066-3C>T

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Interpretation:
Pathogenic/Likely pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
8 (Most recent: Sep 2, 2021)
Last evaluated:
Sep 26, 2020
Accession:
VCV000000623.7
Variation ID:
623
Description:
single nucleotide variant
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NM_000277.3(PAH):c.1066-3C>T

Allele ID
15662
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
12q23.2
Genomic location
12: 102843782 (GRCh38) GRCh38 UCSC
12: 103237560 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000012.11:g.103237560G>A
NC_000012.12:g.102843782G>A
NG_008690.2:g.119629C>T
... more HGVS
Protein change
-
Other names
IVS10AS, C-T, -3
Canonical SPDI
NC_000012.12:102843781:G:A
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00004
Links
ClinGen: CA229324
OMIM: 612349.0049
dbSNP: rs62507344
Varsome
Comment on variant
NCBI staff reviewed the sequence information reported in PubMed 8098245 Fig. 2 determine the location of this allele on the current reference sequence.
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic/Likely pathogenic 5 criteria provided, multiple submitters, no conflicts Sep 26, 2020 RCV000000654.13
Pathogenic 3 criteria provided, single submitter Nov 6, 2014 RCV000088742.3
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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
(Nov 06, 2014)
criteria provided, single submitter
Method: literature only
Phenylketonuria
(Autosomal recessive inheritance)
Allele origin: unknown
Counsyl
Accession: SCV000220862.1
Submitted: (Mar 11, 2015)
Evidence details
Publications
PubMed (16)
Pathogenic
(Nov 06, 2014)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics
Accession: SCV000225209.5
Submitted: (Sep 19, 2018)
Evidence details
Publications
PubMed (5)
Other databases
http://www.egl-eurofins.com/emvc…
http://www.pahdb.mcgill.ca/
Pathogenic
(May 13, 2019)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362284.1
Submitted: (Mar 06, 2020)
Evidence details
Publications
PubMed (3)
Comment:
Variant summary: PAH c.1066-3C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Pathogenic
(Dec 18, 2018)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV000914555.1
Submitted: (Feb 01, 2019)
Evidence details
Publications
PubMed (6)
Comment:
Across a selection of the available literature, the PAH c.1066-3C>T splice region variant has been reported in at least six studies in which it is … (more)
Pathogenic
(Sep 26, 2020)
criteria provided, single submitter
Method: clinical testing
Phenylketonuria
Allele origin: germline
Invitae
Accession: SCV000836557.4
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (11)
Comment:
This sequence change falls in intron 10 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein, … (more)
Pathogenic
(Jan 01, 1993)
no assertion criteria provided
Method: literature only
PHENYLKETONURIA
Allele origin: germline
OMIM
Accession: SCV000020804.2
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (1)
Pathogenic
(Jan 06, 2020)
no assertion criteria provided
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV001822273.1
Submitted: (Sep 02, 2021)
Evidence details
Comment:
Published in vitro study demonstrates the c.1066-3C>T variant results in skipping of exon 11 (Abadie et al., 1993); Not observed at a significant frequency in … (more)
not provided
(-)
no assertion provided
Method: not provided
not provided
Allele origin: not provided
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE
Accession: SCV000119325.1
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
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
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
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
Prevalence of tetrahydrobiopterine (BH4)-responsive alleles among Austrian patients with PAH deficiency: comprehensive results from molecular analysis in 147 patients. Sterl E Journal of inherited metabolic disease 2013 PMID: 22526846
Chaperone-like therapy with tetrahydrobiopterin in clinical trials for phenylketonuria: is genotype a predictor of response? Sarkissian CN JIMD reports 2012 PMID: 23430918
Utility of phenylalanine hydroxylase genotype for tetrahydrobiopterin responsiveness classification in patients with phenylketonuria. Quirk ME Molecular genetics and metabolism 2012 PMID: 22841515
Splicing of phenylalanine hydroxylase (PAH) exon 11 is vulnerable: molecular pathology of mutations in PAH exon 11. Heintz C Molecular genetics and metabolism 2012 PMID: 22698810
Five novel mutations and two large deletions in a population analysis of the phenylalanine hydroxylase gene. Groselj U Molecular genetics and metabolism 2012 PMID: 22513348
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
A limited spectrum of phenylalanine hydroxylase mutations is observed in phenylketonuria patients in western Poland and implications for treatment with 6R tetrahydrobiopterin. Dobrowolski SF Journal of human genetics 2009 PMID: 19444284
Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Zurflüh MR Human mutation 2008 PMID: 17935162
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. Buratti E Nucleic acids research 2007 PMID: 17576681
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
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
Phenylketonuria mutations in Germany. Zschocke J Human genetics 1999 PMID: 10394930
Statistical features of human exons and their flanking regions. Zhang MQ Human molecular genetics 1998 PMID: 9536098
Phenylketonuria mutation analysis in Northern Ireland: a rapid stepwise approach. Zschocke J American journal of human genetics 1995 PMID: 8533759
Illegitimate transcription of the phenylalanine hydroxylase gene in lymphocytes for identification of mutations in phenylketonuria. Abadie V Human molecular genetics 1993 PMID: 8098245
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH - - - -
http://www.pahdb.mcgill.ca/ - - - -

Text-mined citations for rs62507344...

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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