VCV000558152.13 - ClinVar

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

Germline

Classification

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.

(6)

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.

Conflicting classifications of pathogenicity
Pathogenic(3); Likely pathogenic(2); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 558152 Accession: VCV000558152.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q23.1 11: 112228656 (GRCh38) [ NCBI UCSC ] 11: 112099379 (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	Jun 17, 2024	Feb 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000317.3:c.146A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000308.1:p.His49Arg	missense
NC_000011.10:g.112228656A>G
NC_000011.9:g.112099379A>G
NG_008743.1:g.7292A>G

Protein change

H49R

Other names

Canonical SPDI

NC_000011.10:112228655:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

dbSNP: rs750229518 VarSome

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
Gene	OMIM	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
TEX12		-	-	GRCh38 GRCh37	5	24

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.
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Feb 14, 2024	RCV000674378.13
not provided	Pathogenic (1)	criteria provided, single submitter	May 28, 2019	RCV000986136.1

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.
Uncertain significance (May 02, 2018)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000799703.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (2) PubMed: 7563095‚ 20059486
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001135035.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely pathogenic (Sep 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002014492.1 First in ClinVar: Nov 12, 2021 Last updated: Nov 12, 2021
Likely pathogenic (Dec 15, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002819566.1 First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023	Publications: PubMed (5) PubMed: 31332730‚ 20059486‚ 32651154‚ 33234470‚ 33822819 Comment: 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+ … (more) 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. (less)
Pathogenic (Dec 06, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001577430.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 20059486‚ 31332730‚ 33234470‚ 19830588 Comment: 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). … (more) 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. (less)
Pathogenic (Feb 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004207143.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024

Comment:

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.

Comment:

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.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
BH4-deficient hyperphenylalaninemia in Russia.	Gundorova P	PloS one	2021	PMID: 33822819
Retrospective analysis of 19 patients with 6-Pyruvoyl Tetrahydropterin Synthase Deficiency: Prolactin levels inversely correlate with growth.	Manzoni F	Molecular genetics and metabolism	2020	PMID: 33234470
Long-term clinical outcome of 6-pyruvoyl-tetrahydropterin synthase-deficient patients.	Manti F	Molecular genetics and metabolism	2020	PMID: 32651154
The study of the full spectrum of variants leading to hyperphenylalaninemia have revealed 10 new variants in the PAH gene.	Kuznetcova I	Metabolic brain disease	2019	PMID: 31332730
Phenotypic variability, neurological outcome and genetics background of 6-pyruvoyl-tetrahydropterin synthase deficiency.	Leuzzi V	Clinical genetics	2010	PMID: 20059486
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	Journal of inherited metabolic disease	2009	PMID: 19830588
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	Journal of molecular biology	1995	PMID: 7563095

Text-mined citations for rs750229518 ...

These 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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs750229518 ...