Submissions for variant NM_000317.3(PTS):c.370G>T (p.Val124Leu)

gnomAD frequency: 0.00003  dbSNP: rs150726932

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672207	SCV000797288	uncertain significance	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	2018-01-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000672207	SCV000915500	uncertain significance	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	2018-09-14	criteria provided, single submitter	clinical testing	The PTS c.370G>T (p.Val124Leu)missense variant has been reported in a single study in which it is found in a compound heterozygous state with a second missense variant in one individual with a mild presentation of 6-pyruvoyltetrahydropterin synthase deficiency (Dudesek et al. 2000). Control data are unavailable for this variant, which is reported at a frequency of 0.0001454 in the Latino population of the Genome Aggregation Database. Functional studies revealed that p.Val124Leu recombinant protein had no detectable PTPS enzyme activity in COS-1 cells. Based on the limited evidence, the p.Phe56Ile variant is classified as a variant of unknown significance but suspicious for pathogenicity for 6-pyruvoyltetrahydropterin synthase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000672207	SCV000934117	pathogenic	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 124 of the PTS protein (p.Val124Leu). This variant is present in population databases (rs150726932, gnomAD 0.01%). This missense change has been observed in individual(s) with PTPS deficiency (PMID: 11388593, 27243974). 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: 556231). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects PTS function (PMID: 11388593). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000672207	SCV001163279	likely pathogenic	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000672207	SCV001712372	uncertain significance	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	2021-05-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002531311	SCV003738985	uncertain significance	Inborn genetic diseases	2022-01-26	criteria provided, single submitter	clinical testing	The c.370G>T (p.V124L) alteration is located in exon 6 (coding exon 6) of the PTS gene. This alteration results from a G to T substitution at nucleotide position 370, causing the valine (V) at amino acid position 124 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.007% (20/281996) total alleles studied. The highest observed frequency was 0.014% (5/35380) of Latino alleles. This alteration has been reported with a second alteration in PTS, in two patients with a mild form of 6-pyruvoyl-tetrahydropterin synthase deficiency (PTPS) (Dudesek, 2001; Yubero, 2016; Cortès-Saladelafont, 2018). This amino acid position is not well conserved in available vertebrate species. PTPS activity in fibroblast and red blood cells of the patient with p.L26F/p.V124L were low compared to controls (Dudesek, 2001). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV000672207	SCV002078496	likely pathogenic	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	2020-12-22	no assertion criteria provided	clinical testing