NM_000317.3(PTS):c.104A>G (p.Glu35Gly) AND 6-Pyruvoyl-tetrahydrobiopterin synthase deficiency

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Dec 5, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001379602.8

Allele description [Variation Report for NM_000317.3(PTS):c.104A>G (p.Glu35Gly)]

NM_000317.3(PTS):c.104A>G (p.Glu35Gly)

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.104A>G (p.Glu35Gly)

HGVS:

NC_000011.10:g.112228614A>G
NG_008743.1:g.7250A>G
NM_000317.2:c.104A>G
NM_000317.3:c.104A>GMANE SELECT
NP_000308.1:p.Glu35Gly
NC_000011.9:g.112099337A>G
NM_000317.3:c.104A>G

Protein change:

E35G

Links:

dbSNP: rs1328320990

NCBI 1000 Genomes Browser:

rs1328320990

Molecular consequence:

NM_000317.3:c.104A>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
SCV001577429	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 8, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10089284, 18060820, 28492532
SCV003844412	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Feb 7, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18060820, 10089284 Citation Link,
SCV004207158	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 5, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001577429

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 8, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV003844412

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Feb 7, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV004207158

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 5, 2023)

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	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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Outcome and long-term follow-up of 36 patients with tetrahydrobiopterin deficiency.

Jäggi L, Zurflüh MR, Schuler A, Ponzone A, Porta F, Fiori L, Giovannini M, Santer R, Hoffmann GF, Ibel H, Wendel U, Ballhausen D, Baumgartner MR, Blau N.

Mol Genet Metab. 2008 Mar;93(3):295-305. Epub 2007 Dec 3.

PubMed [citation]

PMID:: 18060820

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001577429.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

ClinVar contains an entry for this variant (Variation ID: 1068143). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 35 of the PTS protein (p.Glu35Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with biopterin deficient hyperphenylalanemia (PMID: 10089284, 18060820). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003844412.1

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

Description

Variant summary: PTS c.104A>G (p.Glu35Gly) 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 was absent in 245486 control chromosomes (gnomAD v2.1). c.104A>G has been reported in the literature in compound heterozygous state in individuals affected with 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency (Zekanowski_1998, Jaggi_2008), and in one of these cases it was observed in trans with a pathogenic variant (Jaggi_2008). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as likely pathogenic. 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, SCV004207158.2

#	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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