PAH-specific ACMG/AMP criteria applied: PM2: 8.1e-6 allele frequency in GnomAD, not found in any other databases; PM3: [c.898G>T];[c.1199+1G>C] in a patient with mild hyperphe (180umol/L); PP4_Moderate: Single patient in Sterl 2013, BH4 defect excluded. Also identified in multiple other patients (7 publications linked through ClinVar) (PMID:22526846); PVS1: +1 canonical splice site. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PM3, PP4_Moderate, PVS1).
ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.1199+1G>C
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
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.1199+1G>C
Variation ID: 102557 Accession: VCV000102557.25
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q23.2 12: 102843645 (GRCh38) [ NCBI UCSC ] 12: 103237423 (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 Oct 20, 2024 Aug 27, 2018 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000277.3:c.1199+1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001354304.2:c.1199+1G>C splice donor NC_000012.12:g.102843645C>G NC_000012.11:g.103237423C>G NG_008690.2:g.119766G>C - Protein change
- -
- Other names
-
NM_000277.2(PAH):c.1199+1G>C
- Canonical SPDI
- NC_000012.12:102843644:C:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
- 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 |
1508 | 1631 | |
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
|
Aug 1, 2024 | RCV000088791.11 | |
| Pathogenic (8) |
reviewed by expert panel
|
Aug 27, 2018 | RCV000169248.21 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Aug 27, 2018)
|
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: SCV000852176.4 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
Comment:
PAH-specific ACMG/AMP criteria applied: PM2: 8.1e-6 allele frequency in GnomAD, not found in any other databases; PM3: [c.898G>T];[c.1199+1G>C] in a patient with mild hyperphe (180umol/L); … (more)
PAH-specific ACMG/AMP criteria applied: PM2: 8.1e-6 allele frequency in GnomAD, not found in any other databases; PM3: [c.898G>T];[c.1199+1G>C] in a patient with mild hyperphe (180umol/L); PP4_Moderate: Single patient in Sterl 2013, BH4 defect excluded. Also identified in multiple other patients (7 publications linked through ClinVar) (PMID:22526846); PVS1: +1 canonical splice site. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PM3, PP4_Moderate, PVS1). (less)
|
|
|
Pathogenic
(Sep 03, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000239091.12
First in ClinVar: Jul 18, 2015 Last updated: May 29, 2016 |
Comment:
The c.1199+1 G>C splice site mutation in the PAH gene has been previously reported in association with phenylketonuria (PKU) (PAH Consortium database). This mutation destroys … (more)
The c.1199+1 G>C splice site mutation in the PAH gene has been previously reported in association with phenylketonuria (PKU) (PAH Consortium database). This mutation destroys the canonical splice donor site in intron 11, and is expected to cause abnormal gene splicing. The variant is found in PAH panel(s). (less)
|
|
|
Pathogenic
(Feb 28, 2019)
|
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: SCV001362290.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: The variant, PAH c.1199+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein … (more)
Variant summary: The variant, PAH c.1199+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-06 in 246046 control chromosomes (gnomAD) and as been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria, Zare-Karizi_2011, Dobrowolski_2011, Jeannesson-Thivisol_2015, Liu_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Dobrowolski_2011), however, does not allow convincing conclusions about the variant effect. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Mar 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002581544.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PM3, PP4_MOD, PM2_SUP
|
Number of individuals with the variant: 1
Sex: male
|
|
|
Likely pathogenic
(Jul 19, 2014)
|
criteria provided, single submitter
Method: literature only
|
Phenylketonuria
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220530.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Nov 12, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002790388.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Oct 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000629177.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change affects a donor splice site in intron 11 of the PAH gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 11 of the PAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs62509015, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with phenylketonuria (PMID: 20187763, 22526846, 22763404, 23856132, 24301756, 26351554, 26413448). This variant is also known as IVS11+1G>C. ClinVar contains an entry for this variant (Variation ID: 102557). 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)
|
|
|
Pathogenic
(Nov 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001163713.2
First in ClinVar: Mar 01, 2020 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Aug 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004702167.8
First in ClinVar: Mar 10, 2024 Last updated: Oct 20, 2024 |
Comment:
PAH: PM3:Very Strong, PVS1, PM2, PP4
Number of individuals with the variant: 3
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001463115.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
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: SCV000119378.1
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
The c.1199+1 G>C splice site mutation in the PAH gene has been previously reported in association with phenylketonuria (PKU) (PAH Consortium database). This mutation destroys the canonical splice donor site in intron 11, and is expected to cause abnormal gene splicing. The variant is found in PAH panel(s).
Comment:
Variant summary: The variant, PAH c.1199+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-06 in 246046 control chromosomes (gnomAD) and as been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria, Zare-Karizi_2011, Dobrowolski_2011, Jeannesson-Thivisol_2015, Liu_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Dobrowolski_2011), however, does not allow convincing conclusions about the variant effect. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change affects a donor splice site in intron 11 of the PAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs62509015, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with phenylketonuria (PMID: 20187763, 22526846, 22763404, 23856132, 24301756, 26351554, 26413448). This variant is also known as IVS11+1G>C. ClinVar contains an entry for this variant (Variation ID: 102557). 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:
PAH: PM3:Very Strong, PVS1, PM2, PP4
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:
PAH-specific ACMG/AMP criteria applied: PM2: 8.1e-6 allele frequency in GnomAD, not found in any other databases; PM3: [c.898G>T];[c.1199+1G>C] in a patient with mild hyperphe (180umol/L); PP4_Moderate: Single patient in Sterl 2013, BH4 defect excluded. Also identified in multiple other patients (7 publications linked through ClinVar) (PMID:22526846); PVS1: +1 canonical splice site. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PM3, PP4_Moderate, PVS1).
Comment:
The c.1199+1 G>C splice site mutation in the PAH gene has been previously reported in association with phenylketonuria (PKU) (PAH Consortium database). This mutation destroys the canonical splice donor site in intron 11, and is expected to cause abnormal gene splicing. The variant is found in PAH panel(s).
Comment:
Variant summary: The variant, PAH c.1199+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-06 in 246046 control chromosomes (gnomAD) and as been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria, Zare-Karizi_2011, Dobrowolski_2011, Jeannesson-Thivisol_2015, Liu_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Dobrowolski_2011), however, does not allow convincing conclusions about the variant effect. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change affects a donor splice site in intron 11 of the PAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs62509015, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with phenylketonuria (PMID: 20187763, 22526846, 22763404, 23856132, 24301756, 26351554, 26413448). This variant is also known as IVS11+1G>C. ClinVar contains an entry for this variant (Variation ID: 102557). 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:
PAH: PM3:Very Strong, PVS1, PM2, PP4
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Mutations of the phenylalanine hydroxylase gene in Iranian patients with phenylketonuria. | Biglari A | SpringerPlus | 2015 | PMID: 26413448 |
| Mutation analysis of the phenylalanine hydroxylase gene in Azerbaijani population, a report from West Azerbaijan province of Iran. | Bagheri M | Iranian journal of basic medical sciences | 2015 | PMID: 26351554 |
| A preliminary mutation analysis of phenylketonuria in southwest Iran. | Ajami N | Genetics and molecular research : GMR | 2013 | PMID: 24301756 |
| Mutation spectrum of phenylketonuria in Syrian population: genotype-phenotype correlation. | Murad H | Gene | 2013 | PMID: 23856132 |
| 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 |
| [Mutation analysis of the phenylalanine hydroxylase gene of phenylketonuria patients of Kemerovskaya Oblast' and Saha Republic]. | Baturina OA | TSitologiia i genetika | 2012 | PMID: 23074961 |
| Mutation spectrum of the PAH gene in the PKU patients from Khorasan Razavi province of Iran. | Hamzehloei T | Gene | 2012 | PMID: 22763404 |
| [Mutation analysis of phenylalanine hydroxylase gene in 55 patients with phenylketonuria from Hebei province]. | Lu CX | Zhonghua yi xue za zhi | 2011 | PMID: 22333022 |
| 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 |
| Mutation spectrum of phenylketonuria in Iranian population. | Zare-Karizi Sh | Molecular genetics and metabolism | 2011 | PMID: 20920871 |
| Mutations of the phenylalanine hydroxylase gene in Iranian Azeri Turkish patients with phenylketonuria. | Bonyadi M | Genetic testing and molecular biomarkers | 2010 | PMID: 20187763 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| 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 |
| Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene. | Eisensmith RC | Human mutation | 1992 | PMID: 1301187 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/97e81c3d-c06f-476a-b576-a37317f3f512 | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs62509015 ...
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 Oct 20, 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.