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

dbSNP: rs750229518

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000674378	SCV000799703	uncertain significance	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	2018-05-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000986136	SCV001135035	pathogenic	not provided	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV000674378	SCV001577430	pathogenic	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	2023-12-06	criteria provided, single submitter	clinical testing	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.
Genome-Nilou Lab	RCV000674378	SCV002014492	likely pathogenic	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	2021-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000674378	SCV002819566	likely pathogenic	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	2022-12-15	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000674378	SCV004207143	pathogenic	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	2024-02-14	criteria provided, single submitter	clinical testing