ClinVar Genomic variation as it relates to human health
NM_000317.3(PTS):c.200C>T (p.Thr67Met)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000317.3(PTS):c.200C>T (p.Thr67Met)
Variation ID: 463151 Accession: VCV000463151.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q23.1 11: 112230639 (GRCh38) [ NCBI UCSC ] 11: 112101362 (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 Dec 26, 2017 Apr 15, 2024 Mar 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000317.3:c.200C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000308.1:p.Thr67Met missense NC_000011.10:g.112230639C>T NC_000011.9:g.112101362C>T NG_008743.1:g.9275C>T - Protein change
- T67M
- Other names
- p.Thr67Met
- Canonical SPDI
- NC_000011.10:112230638:C:T
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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
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
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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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PTS | - | - |
GRCh38 GRCh37 |
257 | 324 |
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
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
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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) |
criteria provided, multiple submitters, no conflicts
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Mar 30, 2024 | RCV000546150.26 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 30, 2022 | RCV002281108.9 |
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
(Jan 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002074330.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
Comment:
Variant summary: PTS c.200C>T (p.Thr67Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: PTS c.200C>T (p.Thr67Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251424 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PTS causing 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency (6.8e-05 vs 0.0011), allowing no conclusion about variant significance. c.200C>T has been reported in the literature in multiple individuals affected with 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency (ie. Oppliger_1997, Cordeiro_2018, Almannai_2019, etc). PTPS activity in homozygous patients fibroblasts was <10% that of wild-type (Oppliger_1997). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 30, 2022)
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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: SCV002569709.2
First in ClinVar: Sep 10, 2022 Last updated: Mar 04, 2023 |
Comment:
Western blot analysis of fibroblasts from a patient who was compound heterozygous for T67M and a second missense variant demonstrate no PTPS protein (Oppliger et … (more)
Western blot analysis of fibroblasts from a patient who was compound heterozygous for T67M and a second missense variant demonstrate no PTPS protein (Oppliger et al., 1997); 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: 25758715, 16917893, 22237589, 16850690, 9222757, 25087612, 11388593, 25525159, 19830588, 10585341, 20059486, 9222755, 11694255, 11438997, 25456745, 30275481, 31589614, 32905092, 30109838, 32651154, 33234470, 36004034, 33101986, 32778825, 33977029, 30926181, 34214291, 35098520, 32202960) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004048254.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The PTS c.200C>T; p.Thr67Met variant has previously been reported in the homozygous and compound heterozygous state in several individuals affected with hyperphenylalaninemia (Oppliger T et. … (more)
The PTS c.200C>T; p.Thr67Met variant has previously been reported in the homozygous and compound heterozygous state in several individuals affected with hyperphenylalaninemia (Oppliger T et. al.; Dudesek A et. al.). Experimental studies have shown that this missense change reduces PTS enzymatic activity (Oppliger T et. al.; Dudesek A et. al.). The p.Thr67Met variant is novel (not in any individuals) in 1000 Genomes and has a frequency of 0.007% in the gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Thr at position 67 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Thr67Met in PTS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic (less)
Clinical Features:
Hyperphenylalaninemia (present) , Global developmental delay (present)
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Pathogenic
(Oct 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004207134.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002019565.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000636855.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 67 of the PTS protein (p.Thr67Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 67 of the PTS protein (p.Thr67Met). This variant is present in population databases (rs370340361, gnomAD 0.02%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 9222757, 11388593, 11438997, 11694255, 16850690, 22237589, 25758715). ClinVar contains an entry for this variant (Variation ID: 463151). 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: 9222757, 11388593). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 17, 2024)
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criteria provided, single submitter
Method: research
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6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805001.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Mar 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV004809207.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
A heterozygous missense variation in exon 4 of the PTS gene that results in the amino acid substitution of Methionine for Threonine at codon 67 … (more)
A heterozygous missense variation in exon 4 of the PTS gene that results in the amino acid substitution of Methionine for Threonine at codon 67 was detected. The observed variant c.200C>T (p.Thr67Met) has not been found in 1000 genomes database and has a minor allele frequency of 0.05% and 0.0026% in the gnomAD and Topmed databases. The in silico prediction of the variant is pathogenic by FATHMM, SIFT, Revel and MutationTaster. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a pathogenic. (less)
Clinical Features:
Respiratory distress (present) , Abnormal posturing (present) , Seizure (present)
Age: 0-9 years
Sex: male
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Pathogenic
(Aug 15, 2017)
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no assertion criteria provided
Method: clinical testing
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6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000793385.2
First in ClinVar: Dec 26, 2017 Last updated: Dec 23, 2019 |
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Pathogenic
(Jul 13, 2020)
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no assertion criteria provided
Method: clinical testing
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6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002075551.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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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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6-Pyruvoyltetrahydropterin Synthase Deficiency: Review and Report of 28 Arab Subjects. | Almannai M | Pediatric neurology | 2019 | PMID: 30926181 |
Outcome of Patients With Inherited Neurotransmitter Disorders. | Cordeiro D | The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques | 2018 | PMID: 30109838 |
Prevalence of inherited neurotransmitter disorders in patients with movement disorders and epilepsy: a retrospective cohort study. | Mercimek-Mahmutoglu S | Orphanet journal of rare diseases | 2015 | PMID: 25758715 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
Fast clinical molecular diagnosis of hyperphenylalaninemia using next-generation sequencing-based on a custom AmpliSeq™ panel and Ion Torrent PGM sequencing. | Cao YY | Molecular genetics and metabolism | 2014 | PMID: 25456745 |
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 |
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 |
6-pyruvoyltetrahydropterin synthase deficiency two-case report. | Pangkanon S | Journal of the Medical Association of Thailand = Chotmaihet thangphaet | 2006 | PMID: 16850690 |
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 |
Molecular analysis and long-term follow-up of patients with different forms of 6-pyruvoyl-tetrahydropterin synthase deficiency. | Dudesek A | European journal of pediatrics | 2001 | PMID: 11388593 |
Identification of mutations causing 6-pyruvoyl-tetrahydropterin synthase deficiency in four Italian families. | Oppliger T | Human mutation | 1997 | PMID: 9222757 |
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Text-mined citations for rs370340361 ...
HelpRecord last updated May 27, 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.