ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs150726932
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Total submissions: 7
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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 2021-12-12 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: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". 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
PerkinElmer Genomics RCV000672207 SCV002024770 likely pathogenic 6-Pyruvoyl-tetrahydrobiopterin synthase deficiency 2019-12-18 no assertion criteria provided clinical testing
Natera, Inc. RCV000672207 SCV002078496 likely pathogenic 6-Pyruvoyl-tetrahydrobiopterin synthase deficiency 2020-12-22 no assertion criteria provided clinical testing

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