The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.011%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000479). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 11438997, 8707300). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_000317.3(PTS):c.155A>G (p.Asn52Ser)
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.
(11)
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
11
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.155A>G (p.Asn52Ser)
Variation ID: 479 Accession: VCV000000479.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q23.1 11: 112228665 (GRCh38) [ NCBI UCSC ] 11: 112099388 (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 Oct 23, 2016 Oct 8, 2024 Mar 15, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000317.3:c.155A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000308.1:p.Asn52Ser missense NC_000011.10:g.112228665A>G NC_000011.9:g.112099388A>G NG_008743.1:g.7301A>G Q03393:p.Asn52Ser - Protein change
- N52S
- Other names
- -
- Canonical SPDI
- NC_000011.10:112228664:A: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.
-
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00012
Exome Aggregation Consortium (ExAC) 0.00015
- 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 (9) |
criteria provided, multiple submitters, no conflicts
|
Mar 15, 2024 | RCV000000508.29 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 29, 2022 | RCV003156211.8 | |
|
PTS-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Nov 20, 2023 | RCV003924789.2 |
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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|---|---|---|---|---|---|
|
Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841776.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.011%). Missense changes are a common disease-causing mechanism. … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.011%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000479). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 11438997, 8707300). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Global developmental delay (present) , Hyperphenylalaninemia (present) , Dystonic disorder (present) , Oculogyric crisis (present) , Generalized hypotonia (present) , Hyperhidrosis (present) , Sleep abnormality … (more)
Global developmental delay (present) , Hyperphenylalaninemia (present) , Dystonic disorder (present) , Oculogyric crisis (present) , Generalized hypotonia (present) , Hyperhidrosis (present) , Sleep abnormality (present) , Abnormal circulating neopterin concentration (present) , Abnormal circulating biopterin concentration (present) (less)
|
|
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Pathogenic
(Jul 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002019566.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Apr 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003845641.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17407085, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17407085, 25304915, 25456745, 29961769, 19350512, 11438997, 20059486, 9450907, 8707300, 22237589, 11694255, 27246466, 30926181, 30275481, 31589614, 32651154, 33234470, 33822819, 23138986) (less)
|
|
|
Pathogenic
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000636854.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 52 of the PTS protein (p.Asn52Ser). … (more)
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 52 of the PTS protein (p.Asn52Ser). This variant is present in population databases (rs104894275, gnomAD 0.1%). This missense change has been observed in individuals with PTS deficiency (PMID: 8707300, 9450907, 11438997, 17160954). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 479). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PTS function (PMID: 23138986). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
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: SCV005051947.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Mar 15, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004207140.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001452591.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(Nov 20, 2023)
|
no assertion criteria provided
Method: clinical testing
|
PTS-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004740073.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The PTS c.155A>G variant is predicted to result in the amino acid substitution p.Asn52Ser. This variant has been reported in the homozygous state or with … (more)
The PTS c.155A>G variant is predicted to result in the amino acid substitution p.Asn52Ser. This variant has been reported in the homozygous state or with a second PTS variant in patients with 6-pyruvoyltetrahydropterin syntase (PTPS) deficiency syndrome (for example, see Leuzzi et al. 2010. PubMed ID: 20059486; Almannai et al. 2019. PubMed ID: 30926181; Manzoni et al. 2020. PubMed ID: 33234470). This variant is one of the most commonly reported causative variants for PTPS deficiency in Asian populations (Liu and Hsiao 1996. PubMed ID: 8707300; Liu et al. 2001. PubMed ID: 11694255; Chiu et al. 2012. PubMed ID: 22237589). This variant is reported in 0.14% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-112099388-A-G). This variant is interpreted as pathogenic. (less)
|
|
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Pathogenic
(Jan 01, 1998)
|
no assertion criteria provided
Method: literature only
|
HYPERPHENYLALANINEMIA, BH4-DEFICIENT, A
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020657.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2016 |
Comment on evidence:
In a study of 19 unrelated Chinese families with BH4-deficient hyperphenylalaninemia due to PTS deficiency (261640), Liu et al. (1998) found that an asn52-to-ser (N52S) … (more)
In a study of 19 unrelated Chinese families with BH4-deficient hyperphenylalaninemia due to PTS deficiency (261640), Liu et al. (1998) found that an asn52-to-ser (N52S) mutation in the PTS gene accounted for 48% of southern Chinese mutations but only 1 (9%) of northern Chinese mutant alleles. The allele was associated with severe clinical symptoms. (less)
|
|
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Uncertain significance
(Jun 07, 2017)
|
no assertion criteria provided
Method: curation
|
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Affected status: no
Allele origin:
germline
|
SingHealth Duke-NUS Institute of Precision Medicine
Accession: SCV000853173.1
First in ClinVar: Nov 25, 2018 Last updated: Nov 25, 2018 |
|
|
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Pathogenic
(Jan 29, 2019)
|
no assertion criteria provided
Method: clinical testing
|
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000790852.2
First in ClinVar: Dec 26, 2017 Last updated: Dec 23, 2019 |
|
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| click to load more click to collapse | |||||
Comment:
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17407085, 25304915, 25456745, 29961769, 19350512, 11438997, 20059486, 9450907, 8707300, 22237589, 11694255, 27246466, 30926181, 30275481, 31589614, 32651154, 33234470, 33822819, 23138986)
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 52 of the PTS protein (p.Asn52Ser). This variant is present in population databases (rs104894275, gnomAD 0.1%). This missense change has been observed in individuals with PTS deficiency (PMID: 8707300, 9450907, 11438997, 17160954). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 479). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PTS function (PMID: 23138986). For these reasons, this variant has been classified as Pathogenic.
Comment:
The PTS c.155A>G variant is predicted to result in the amino acid substitution p.Asn52Ser. This variant has been reported in the homozygous state or with a second PTS variant in patients with 6-pyruvoyltetrahydropterin syntase (PTPS) deficiency syndrome (for example, see Leuzzi et al. 2010. PubMed ID: 20059486; Almannai et al. 2019. PubMed ID: 30926181; Manzoni et al. 2020. PubMed ID: 33234470). This variant is one of the most commonly reported causative variants for PTPS deficiency in Asian populations (Liu and Hsiao 1996. PubMed ID: 8707300; Liu et al. 2001. PubMed ID: 11694255; Chiu et al. 2012. PubMed ID: 22237589). This variant is reported in 0.14% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-112099388-A-G). This variant is interpreted 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 variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.011%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000479). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 11438997, 8707300). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17407085, 25304915, 25456745, 29961769, 19350512, 11438997, 20059486, 9450907, 8707300, 22237589, 11694255, 27246466, 30926181, 30275481, 31589614, 32651154, 33234470, 33822819, 23138986)
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 52 of the PTS protein (p.Asn52Ser). This variant is present in population databases (rs104894275, gnomAD 0.1%). This missense change has been observed in individuals with PTS deficiency (PMID: 8707300, 9450907, 11438997, 17160954). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 479). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PTS function (PMID: 23138986). For these reasons, this variant has been classified as Pathogenic.
Comment:
The PTS c.155A>G variant is predicted to result in the amino acid substitution p.Asn52Ser. This variant has been reported in the homozygous state or with a second PTS variant in patients with 6-pyruvoyltetrahydropterin syntase (PTPS) deficiency syndrome (for example, see Leuzzi et al. 2010. PubMed ID: 20059486; Almannai et al. 2019. PubMed ID: 30926181; Manzoni et al. 2020. PubMed ID: 33234470). This variant is one of the most commonly reported causative variants for PTPS deficiency in Asian populations (Liu and Hsiao 1996. PubMed ID: 8707300; Liu et al. 2001. PubMed ID: 11694255; Chiu et al. 2012. PubMed ID: 22237589). This variant is reported in 0.14% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-112099388-A-G). This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Demographics, diagnosis and treatment of 256 patients with tetrahydrobiopterin deficiency in mainland China: results of a retrospective, multicentre study. | Ye J | Journal of inherited metabolic disease | 2013 | PMID: 23138986 |
| Mutation spectrum of and founder effects affecting the PTS gene in East Asian populations. | Chiu YH | Journal of human genetics | 2012 | PMID: 22237589 |
| Phenotypic variability, neurological outcome and genetics background of 6-pyruvoyl-tetrahydropterin synthase deficiency. | Leuzzi V | Clinical genetics | 2010 | PMID: 20059486 |
| [Detection of the prevalent mutations of 6-pyruvoyl-tetrahydropterin synthase gene by PCR-RFLP analysis in Chinese patients]. | Qu YJ | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2006 | PMID: 17160954 |
| Tetrahydrobiopterin-deficient hyperphenylalaninemia in the Chinese. | Liu TT | Clinica chimica acta; international journal of clinical chemistry | 2001 | PMID: 11694255 |
| Identification of three novel 6-pyruvoyl-tetrahydropterin synthase gene mutations (226C>T, IVS3+1G>A, 116-119delTGTT) in Chinese hyperphenylalaninemia caused by tetrahydrobiopterin synthesis deficiency. | Liu TT | Human mutation | 2001 | PMID: 11438997 |
| Mutation analysis of the 6-pyruvoyl-tetrahydropterin synthase gene in Chinese hyperphenylalaninemia caused by tetrahydrobiopterin synthesis deficiency. | Liu TT | Human mutation | 1998 | PMID: 9450907 |
| Identification of a common 6-pyruvoyl-tetrahydropterin synthase mutation at codon 87 in Chinese phenylketonuria caused by tetrahydrobiopterin synthesis deficiency. | Liu TT | Human genetics | 1996 | PMID: 8707300 |
Text-mined citations for rs104894275 ...
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.