The c.913-7A>G variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded) PMID: 9634518, 16601866. This variant has extremely low frequency in gnomAD (MAF=0.00003). This variant was detected with 10 different variants for a total of 3.75 points (PM3_Strong. Computational evidence predicts splicing changes. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_Strong, PP3.
ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.913-7A>G
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Likely pathogenic
for
Phenylketonuria
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000277.3(PAH):c.913-7A>G
Variation ID: 102894 Accession: VCV000102894.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q23.2 12: 102846958 (GRCh38) [ NCBI UCSC ] 12: 103240736 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Feb 20, 2024 Feb 16, 2020 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000277.3:c.913-7A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001354304.2:c.913-7A>G intron variant NC_000012.12:g.102846958T>C NC_000012.11:g.103240736T>C NG_008690.2:g.116453A>G - Protein change
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- Other names
- -
- Canonical SPDI
- NC_000012.12:102846957:T:C
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| PAH | - | - |
GRCh38 GRCh37 |
1506 | 1629 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 12, 2019 | RCV000089156.6 | |
| Likely pathogenic (7) |
reviewed by expert panel
|
Feb 16, 2020 | RCV000589029.13 |
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
Help
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
Help
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
Help
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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Likely pathogenic
(Feb 16, 2020)
|
reviewed by expert panel
Method: curation
|
Phenylketonuria
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen PAH Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV001370819.1 First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
The c.913-7A>G variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded) PMID: 9634518, 16601866. This variant has extremely low … (more)
The c.913-7A>G variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded) PMID: 9634518, 16601866. This variant has extremely low frequency in gnomAD (MAF=0.00003). This variant was detected with 10 different variants for a total of 3.75 points (PM3_Strong. Computational evidence predicts splicing changes. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_Strong, PP3. (less)
|
|
|
Pathogenic
(Nov 18, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000703341.2
First in ClinVar: Mar 17, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Pathogenic
(Nov 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001470580.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
Found in at least one patient with expected phenotype for this gene. Predicted to negatively affect a known splice site, causing an out-of-frame effect. Low … (more)
Found in at least one patient with expected phenotype for this gene. Predicted to negatively affect a known splice site, causing an out-of-frame effect. Low nucleotide conservation. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. (less)
|
|
|
Likely pathogenic
(Jul 12, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893938.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Sep 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004209594.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
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Pathogenic
(Jan 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001580108.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change falls in intron 8 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 8 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. This variant is present in population databases (rs62517165, gnomAD 0.003%). This variant has been observed in individual(s) with phenylketonuria (PKU) (PMID: 26600521, 29499199, 29653233). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS8-7A>G. ClinVar contains an entry for this variant (Variation ID: 102894). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Apr 18, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696472.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: Variant affects a non-conserved nucleotide located in close proximity of an exon-intron boundary. 5/5 in silico tools predict the variant to create a … (more)
Variant summary: Variant affects a non-conserved nucleotide located in close proximity of an exon-intron boundary. 5/5 in silico tools predict the variant to create a splice acceptor site7 nucleotides upstream of the intron 8/ exon 9 splice junction. The variant was observed in the general population by the ExAC project at an allele frequency of 0.00082% which does not exceed the maximal expected allele frequency of a disease causing PAH allele (~0.8%). It was reported in several PKU/HPA patients with a second pathogenic mutation on the other allele indicating pathogenicity. HGMD lists variant as Pathogenic. Considering all evidence, the variant was classified as Pathogenic. (less)
|
|
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Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001463132.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Likely pathogenic
(May 19, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000791679.2
First in ClinVar: Mar 17, 2018 Last updated: Mar 31, 2019 |
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE
Accession: SCV000119770.1
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
|
Comment:
Comment:
Found in at least one patient with expected phenotype for this gene. Predicted to negatively affect a known splice site, causing an out-of-frame effect. Low nucleotide conservation. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Comment:
This sequence change falls in intron 8 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. This variant is present in population databases (rs62517165, gnomAD 0.003%). This variant has been observed in individual(s) with phenylketonuria (PKU) (PMID: 26600521, 29499199, 29653233). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS8-7A>G. ClinVar contains an entry for this variant (Variation ID: 102894). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: Variant affects a non-conserved nucleotide located in close proximity of an exon-intron boundary. 5/5 in silico tools predict the variant to create a splice acceptor site7 nucleotides upstream of the intron 8/ exon 9 splice junction. The variant was observed in the general population by the ExAC project at an allele frequency of 0.00082% which does not exceed the maximal expected allele frequency of a disease causing PAH allele (~0.8%). It was reported in several PKU/HPA patients with a second pathogenic mutation on the other allele indicating pathogenicity. HGMD lists variant as Pathogenic. Considering all evidence, the variant was classified as Pathogenic.
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. |
Comment:
The c.913-7A>G variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded) PMID: 9634518, 16601866. This variant has extremely low frequency in gnomAD (MAF=0.00003). This variant was detected with 10 different variants for a total of 3.75 points (PM3_Strong. Computational evidence predicts splicing changes. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_Strong, PP3.
Comment:
Found in at least one patient with expected phenotype for this gene. Predicted to negatively affect a known splice site, causing an out-of-frame effect. Low nucleotide conservation. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Comment:
This sequence change falls in intron 8 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. This variant is present in population databases (rs62517165, gnomAD 0.003%). This variant has been observed in individual(s) with phenylketonuria (PKU) (PMID: 26600521, 29499199, 29653233). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS8-7A>G. ClinVar contains an entry for this variant (Variation ID: 102894). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: Variant affects a non-conserved nucleotide located in close proximity of an exon-intron boundary. 5/5 in silico tools predict the variant to create a splice acceptor site7 nucleotides upstream of the intron 8/ exon 9 splice junction. The variant was observed in the general population by the ExAC project at an allele frequency of 0.00082% which does not exceed the maximal expected allele frequency of a disease causing PAH allele (~0.8%). It was reported in several PKU/HPA patients with a second pathogenic mutation on the other allele indicating pathogenicity. HGMD lists variant as Pathogenic. Considering all evidence, the variant was classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Three novel variants (p.Glu178Lys, p.Val245Met, p.Ser250Phe) of the phenylalanine hydroxylase (PAH) gene impair protein expression and function in vitro. | Zong Y | Gene | 2018 | PMID: 29653233 |
| Mutation spectrum of hyperphenylalaninemia candidate genes and the genotype-phenotype correlation in the Chinese population. | Wang R | Clinica chimica acta; international journal of clinical chemistry | 2018 | PMID: 29499199 |
| 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 |
| Prenatal diagnosis of Chinese families with phenylketonuria. | Liu N | Genetics and molecular research : GMR | 2015 | PMID: 26600521 |
| Correlation between genotype and the tetrahydrobiopterin-responsive phenotype in Chinese patients with phenylketonuria. | Tao J | Pediatric research | 2015 | PMID: 26322415 |
| The mutation spectrum of the phenylalanine hydroxylase (PAH) gene and associated haplotypes reveal ethnic heterogeneity in the Taiwanese population. | Liang Y | Journal of human genetics | 2014 | PMID: 24401910 |
| Splice, insertion-deletion and nonsense mutations that perturb the phenylalanine hydroxylase transcript cause phenylketonuria in India. | Bashyam MD | Journal of cellular biochemistry | 2014 | PMID: 24130151 |
| Mutation analysis of PAH gene in patients with PKU in western Iran and its association with polymorphisms: identification of four novel mutations. | Alibakhshi R | Metabolic brain disease | 2014 | PMID: 24048906 |
| 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 |
| Chaperone-like therapy with tetrahydrobiopterin in clinical trials for phenylketonuria: is genotype a predictor of response? | Sarkissian CN | JIMD reports | 2012 | PMID: 23430918 |
| 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 |
| The spectrum of phenylalanine variations under tetrahydrobiopterin load in subjects affected by phenylalanine hydroxylase deficiency. | Leuzzi V | Journal of inherited metabolic disease | 2006 | PMID: 16601866 |
| Phenylketonuria mutations in Northern China. | Song F | Molecular genetics and metabolism | 2005 | PMID: 16256386 |
| 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 |
| Biochemical phenotype and its relationship with genotype in hyperphenylalaninemia heterozygotes. | Mallolas J | Molecular genetics and metabolism | 1999 | PMID: 10356315 |
| 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 |
| Analysis of the phenylalanine hydroxylase gene in the Spanish population: mutation profile and association with intragenic polymorphic markers. | Pérez B | American journal of human genetics | 1997 | PMID: 8981952 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b4ecce45-4b5e-464f-be37-d7949b576c34 | - | - | - | - |
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Text-mined citations for rs62517165 ...
HelpThese 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 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.