NM_000317.3(PTS):c.146A>G (p.His49Arg) AND 6-Pyruvoyl-tetrahydrobiopterin synthase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Feb 14, 2024
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:: RCV000674378.13

Allele description [Variation Report for NM_000317.3(PTS):c.146A>G (p.His49Arg)]

NM_000317.3(PTS):c.146A>G (p.His49Arg)

Genes:

TEX12:testis expressed 12 [Gene - OMIM - HGNC]
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.146A>G (p.His49Arg)

HGVS:

NC_000011.10:g.112228656A>G
NG_008743.1:g.7292A>G
NM_000317.3:c.146A>GMANE SELECT
NP_000308.1:p.His49Arg
NC_000011.9:g.112099379A>G
NM_000317.2:c.146A>G

Protein change:

H49R

Links:

dbSNP: rs750229518

NCBI 1000 Genomes Browser:

rs750229518

Molecular consequence:

NM_000317.3:c.146A>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000799703	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (May 2, 2018)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 7563095, 20059486 Citation Link,
SCV001577430	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 6, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20059486, 31332730, 33234470, 19830588, 28492532
SCV002014492	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]
SCV002819566	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Dec 15, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 31332730, 20059486, 32651154, 33234470, 33822819 Citation Link,
SCV004207143	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 14, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

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

6-Pyruvoyl tetrahydropterin synthase, an enzyme with a novel type of active site involving both zinc binding and an intersubunit catalytic triad motif; site-directed mutagenesis of the proposed active center, characterization of the metal binding site and modelling of substrate binding.

Bürgisser DM, Thöny B, Redweik U, Hess D, Heizmann CW, Huber R, Nar H.

J Mol Biol. 1995 Oct 20;253(2):358-69.

PubMed [citation]

PMID:: 7563095

Novel mutation affecting the pterin-binding site of PTS gene and review of PTS mutations in Thai patients with 6-pyruvoyltetrahydropterin synthase deficiency.

Vatanavicharn N, Kuptanon C, Liammongkolkul S, Liu TT, Hsiao KJ, Ratanarak P, Blau N, Wasant P.

J Inherit Metab Dis. 2009 Dec;32 Suppl 1:S279-82. doi: 10.1007/s10545-009-1221-x. Epub 2009 Oct 13. Review.

PubMed [citation]

PMID:: 19830588

See all PubMed Citations (9)

Details of each submission

From Counsyl, SCV000799703.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	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, SCV001577430.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 49 of the PTS protein (p.His49Arg). This variant is present in population databases (rs750229518, gnomAD 0.01%). This missense change has been observed in individual(s) with 6-pyruvoyl-tetrahydropterin synthase deficiency and/or biopterin-deficient hyperphenylalaninemia (PMID: 20059486, 31332730, 33234470). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 558152). 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. This variant disrupts the p.His49 amino acid residue in PTS. Other variant(s) that disrupt this residue have been observed in individuals with PTS-related conditions (PMID: 19830588), which suggests that this may be a clinically significant amino acid residue. 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, SCV002014492.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002819566.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: PTS c.146A>G (p.His49Arg) results in a non-conservative amino acid change located in the 6-pyruvoyl tetrahydropterin synthase, cysteine active site (IPR022470), affecting a Zn2+ binding site (UniProt) 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 1.6e-05 in 250414 control chromosomes (gnomAD). c.146A>G has been reported in the literature in multiple compound heterozygous individuals affected with 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency (Leuzzi_2009, Manti_2020, Manzoni_2020, Kuznetcova_2019, Gundorova_2021), where at least one individual had PTS enzyme deficiency, as measured in patient derived cells (Manzoni_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely 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 Baylor Genetics, SCV004207143.2

#	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: Sep 29, 2024

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