NM_000317.3(PTS):c.400G>T (p.Glu134Ter) AND 6-Pyruvoyl-tetrahydrobiopterin synthase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Dec 6, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000671217.23

Allele description [Variation Report for NM_000317.3(PTS):c.400G>T (p.Glu134Ter)]

NM_000317.3(PTS):c.400G>T (p.Glu134Ter)

Gene:

PTS:6-pyruvoyltetrahydropterin synthase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q23.1

Genomic location:

Preferred name:

NM_000317.3(PTS):c.400G>T (p.Glu134Ter)

HGVS:

NC_000011.10:g.112233517G>T
NG_008743.1:g.12153G>T
NM_000317.3:c.400G>TMANE SELECT
NP_000308.1:p.Glu134Ter
NC_000011.9:g.112104240G>T
NM_000317.2:c.400G>T

Protein change:

E134*

Links:

dbSNP: rs779681799

NCBI 1000 Genomes Browser:

rs779681799

Molecular consequence:

NM_000317.3:c.400G>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: 6-Pyruvoyl-tetrahydrobiopterin synthase deficiency
Synonyms:: HYPERPHENYLALANINEMIA, TETRAHYDROBIOPTERIN-DEFICIENT, DUE TO PTS DEFICIENCY; 6-pyruvoyl-tetrahydropterin synthase deficiency; Hyperphenylalanemia, BH4-deficient, A; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009863; MedGen: C0878676; Orphanet: 13; Orphanet: 238583; OMIM: 261640

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000796170	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Dec 4, 2017)	unknown	clinical testing	Citation Link,
SCV001575567	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 26, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9222757, 11388593, 25418970, 28492532
SCV002014496	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 5, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002078518	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Aug 18, 2021)	germline	clinical testing
SCV004207155	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 6, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of mutations causing 6-pyruvoyl-tetrahydropterin synthase deficiency in four Italian families.

Oppliger T, Thöny B, Kluge C, Matasovic A, Heizmann CW, Ponzone A, Spada M, Blau N.

Hum Mutat. 1997;10(1):25-35.

PubMed [citation]

PMID:: 9222757

Molecular analysis and long-term follow-up of patients with different forms of 6-pyruvoyl-tetrahydropterin synthase deficiency.

Dudesek A, Röschinger W, Muntau AC, Seidel J, Leupold D, Thöny B, Blau N.

Eur J Pediatr. 2001 May;160(5):267-76.

PubMed [citation]

PMID:: 11388593

See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000796170.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001575567.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Glu134*) in the PTS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 12 amino acid(s) of the PTS protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PTS-related conditions. ClinVar contains an entry for this variant (Variation ID: 555399). This variant disrupts a region of the PTS protein in which other variant(s) (p.Asp136Val) have been determined to be pathogenic (PMID: 9222757, 11388593, 25418970; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002014496.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002078518.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004207155.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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