ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.1066-3C>T
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000277.3(PAH):c.1066-3C>T
Variation ID: 623 Accession: VCV000000623.99
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q23.2 12: 102843782 (GRCh38) [ NCBI UCSC ] 12: 103237560 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 19, 2014 Jun 17, 2024 Dec 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000277.3:c.1066-3C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001354304.2:c.1066-3C>T intron variant NC_000012.12:g.102843782G>A NC_000012.11:g.103237560G>A NG_008690.2:g.119629C>T - Protein change
- Other names
- NM_000277.1(PAH):c.1066-3C>T
- IVS10AS, C-T, -3
- Canonical SPDI
- NC_000012.12:102843781:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00004
- Comment on variant
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PAH | - | - |
GRCh38 GRCh37 |
1504 | 1627 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (9) |
reviewed by expert panel
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Dec 30, 2023 | RCV000000654.95 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 6, 2020 | RCV000088742.13 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Dec 30, 2023)
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reviewed by expert panel
Method: curation
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Phenylketonuria
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen PAH Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV004222617.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The c.1066-3C>T variant in PAH has been reported in multiple individuals with Classic PKU and MHP (BH4 deficiency excluded). (PMID: 9634518, 27121329). It has been … (more)
The c.1066-3C>T variant in PAH has been reported in multiple individuals with Classic PKU and MHP (BH4 deficiency excluded). (PMID: 9634518, 27121329). It has been detected with multiple pathogenic variants: c.1222C>T (p.Arg408Trp) (in trans, PMID: 27121329); c.1315+1G>A (PMID: 17502162); p.G272X, p.S310F (PMID: 23430918); c.194T>C (p.I65T), c.1208C>T (p.A403V), c.398_401del (p.N133fs), c.1222C>T (p.R408W) 2 patients, c.165delT (p.F55fs), c.168+5G>C (IVS2+5G>C) (PMID: 22526846). This variant has an extremely low allele frequency in ExAC and gnomAD (MAF=0.00014). This variant has 0% enzyme activity. This variant resulted in the skipping of exon 11 with the premature termination of RNA translation downstream from exon 12 (PMID: 8098245). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PP4_Moderate, PM2_supporting. (less)
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Pathogenic
(May 13, 2019)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362284.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
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)
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 altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 3' acceptor site and two predict the variant weakens a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing leading to exon 11 skipping (Heintz_2012). The variant allele was found at a frequency of 4e-05 in 250904 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (4e-05 vs 0.0079), allowing no conclusion about variant significance. c.1066-3C>T has been reported in the literature in multiple individuals affected with Phenylketonuria and Hyperphenylalaninemia (Heintz_2012, Reblova_2013, Sterl_2013). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 06, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001822273.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
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)
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 large population cohorts (Lek et al., 2016); Responsiveness to tetrahydrobiopterin (BH4) therapy is not clear (Sarkissian et al., 2012); This variant is associated with the following publications: (PMID: 33101986, 32668217, 31589614, 22526846, 8098245, 29288420, 26666653, 24368688, 7657610, 15464430, 22513348, 21147011, 22698810, 22841515, 23430918, 23672685) (less)
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Likely pathogenic
(Nov 06, 2014)
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criteria provided, single submitter
Method: literature only
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Phenylketonuria
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220862.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Nov 06, 2014)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000225209.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(Dec 18, 2018)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914555.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
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)
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 found in a total of 15 probands including one in a homozygous state and 14 in a compound heterozygous state (Abadie et al. 1993; Dobrowolski et al. 2009; Heintz et al. 2012; Sterl et al. 2013; Ho et al. 2014; Jeannesson-Thivisol et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00019 in the European (Finnish) population of the Genome Aggregation Database. Liver biopsy from a compound heterozygous proband found 1.5% of normal PAH activity (Abadie et al. 1993). RT-PCR of proband derived lymphoblast cells indicated exon 11 skipping and COS-1 cells transfected with minigenes confirmed c.1066-3C>T as the cause of exon 11 skipping (Heintz et al. 2012). Based on the evidence, the c.1066-3C>T variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Jan 02, 2024)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000836557.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
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)
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. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs62507344, gnomAD 0.02%). This variant has been observed in individual(s) with mild hyperphenylalaninemia and phenylketonuria (PMID: 8098245, 17502162, 19444284, 22526846, 22698810, 23357515, 24368688, 26666653). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 623). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 8098245, 22698810). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: curation
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Phenylketonuria
Affected status: no
Allele origin:
germline
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051907.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Pathogenic
(Mar 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004201381.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Jan 01, 1993)
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no assertion criteria provided
Method: literature only
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PHENYLKETONURIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020804.66
First in ClinVar: Apr 04, 2013 Last updated: May 01, 2024 |
Comment on evidence:
In a French patient with a mild form of phenylketonuria (PKU; 261600), Abadie et al. (1993) found deletion of exon 11 due to a C-to-T … (more)
In a French patient with a mild form of phenylketonuria (PKU; 261600), Abadie et al. (1993) found deletion of exon 11 due to a C-to-T transition at the first nucleotide of the splice acceptor triplet of intron 10. The mother was heterozygous for the mutation. The other allele was the R261Q mutation (612349.0006), which has also been associated with mild phenylketonuria and in this case was inherited from the father. (less)
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Pathogenic
(Feb 19, 2021)
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no assertion criteria provided
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002088631.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE
Accession: SCV000119325.1
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
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Germline Functional Evidence
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 germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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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/ | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/5fdcac0d-7ea8-4beb-bec5-bc97c75be7af | - | - | - | - |
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Text-mined citations for rs62507344 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.
NCBI staff reviewed the sequence information reported in PubMed 8098245 Fig. 2 determine the location of this allele on the current reference sequence.