Published functional studies demonstrate that this variant results in complete inactivity of the PTPS enzyme (Oppliger et al., 1997) In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect, and predicts abnormal gene splicing Not observed in large population cohorts (Lek et al., 2016) This variant is associated with the following publications: (PMID: 9222757, 20059486, 10585341, 27246466, 25525159)
ClinVar Genomic variation as it relates to human health
NM_000317.3(PTS):c.84-3C>G
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000317.3(PTS):c.84-3C>G
Variation ID: 553378 Accession: VCV000553378.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q23.1 11: 112228591 (GRCh38) [ NCBI UCSC ] 11: 112099314 (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 Aug 5, 2018 Oct 20, 2024 Feb 1, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000317.3:c.84-3C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000011.10:g.112228591C>G NC_000011.9:g.112099314C>G NG_008743.1:g.7227C>G - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000011.10:112228590:C:G
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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.
-
The Genome Aggregation Database (gnomAD) 0.00002
- 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. |
|||
| PTS | - | - |
GRCh38 GRCh37 |
263 | 331 | |
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/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000668809.21 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 23, 2020 | RCV001091030.33 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Aug 22, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000793473.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446717.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Abnormality of eye movement (present) , Hypotonia (present) , Dystonic disorder (present)
Sex: male
|
|
|
Pathogenic
(Mar 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001791313.1
First in ClinVar: Aug 18, 2021 Last updated: Aug 18, 2021 |
Comment:
Published functional studies demonstrate that this variant results in complete inactivity of the PTPS enzyme (Oppliger et al., 1997) In silico analysis, which includes splice … (more)
Published functional studies demonstrate that this variant results in complete inactivity of the PTPS enzyme (Oppliger et al., 1997) In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect, and predicts abnormal gene splicing Not observed in large population cohorts (Lek et al., 2016) This variant is associated with the following publications: (PMID: 9222757, 20059486, 10585341, 27246466, 25525159) (less)
|
|
|
Pathogenic
(Sep 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002014497.1
First in ClinVar: Nov 12, 2021 Last updated: Nov 12, 2021 |
|
|
|
Pathogenic
(Aug 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000814118.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
Experimental studies have shown that this variant affects PTS function (PMID: 9222757). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt … (more)
Experimental studies have shown that this variant affects PTS function (PMID: 9222757). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 553378). This variant is also known as delK29-S32. This variant has been observed in individual(s) with biopterin deficient hyperphenylalaninemia (PMID: 9222757, 27246466). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 1 of the PTS gene. It does not directly change the encoded amino acid sequence of the PTS protein. It affects a nucleotide within the consensus splice site. (less)
|
|
|
Pathogenic
(Jan 20, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004207151.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Aug 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246862.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: curation
|
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Affected status: no
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051948.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Dec 03, 2020)
|
no assertion criteria provided
Method: clinical testing
|
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002083332.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
|
Comment:
Comment:
Experimental studies have shown that this variant affects PTS function (PMID: 9222757). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 553378). This variant is also known as delK29-S32. This variant has been observed in individual(s) with biopterin deficient hyperphenylalaninemia (PMID: 9222757, 27246466). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 1 of the PTS gene. It does not directly change the encoded amino acid sequence of the PTS protein. It affects a nucleotide within the consensus splice site.
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:
Published functional studies demonstrate that this variant results in complete inactivity of the PTPS enzyme (Oppliger et al., 1997) In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect, and predicts abnormal gene splicing Not observed in large population cohorts (Lek et al., 2016) This variant is associated with the following publications: (PMID: 9222757, 20059486, 10585341, 27246466, 25525159)
Comment:
Experimental studies have shown that this variant affects PTS function (PMID: 9222757). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 553378). This variant is also known as delK29-S32. This variant has been observed in individual(s) with biopterin deficient hyperphenylalaninemia (PMID: 9222757, 27246466). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 1 of the PTS gene. It does not directly change the encoded amino acid sequence of the PTS protein. It affects a nucleotide within the consensus splice site.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Phenotypic variability, neurological outcome and genetics background of 6-pyruvoyl-tetrahydropterin synthase deficiency. | Leuzzi V | Clinical genetics | 2010 | PMID: 20059486 |
| 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 |
| Single-step mutation scanning of the 6-pyruvoyltetrahydropterin synthase gene in patients with hyperphenylalaninemia. | Romstad A | Clinical chemistry | 1999 | PMID: 10585341 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
| Identification of mutations causing 6-pyruvoyl-tetrahydropterin synthase deficiency in four Italian families. | Oppliger T | Human mutation | 1997 | PMID: 9222757 |
Text-mined citations for rs1230781262 ...
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 Nov 25, 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.