Submissions for variant NM_000317.3(PTS):c.238A>G (p.Met80Val)

dbSNP: rs1057517810

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413378	SCV000490757	likely pathogenic	not provided	2016-02-15	criteria provided, single submitter	clinical testing	The M80V missense substitution has not been published as pathogenic, nor has it been reported asa benign polymorphism to our knowledge. However a missense variant at the same position,M80T, has been published in association with 6-pyruvoyltetrahydropterin synthase (PTS)deficiency according to the Human Gene Mutation Database (Ye et al., 2013). The M80V variantis a conservative amino acid substitution, which is not likely to impact secondary protein structureas these residues share similar properties. This substitution occurs at a position where amino acidswith similar properties to Methionine are tolerated across species. An apparently homozygousM80V missense change has been identified in other patients suspected to have PTS deficiencywho were tested at GeneDx. Therefore, based on this information, M80V is a strong candidate fora pathogenic variant, however, the possibility that it is a rare benign variant cannot beexcluded.
Pathology and Clinical Laboratory Medicine, King Fahad Medical City	RCV001261646	SCV001438945	likely pathogenic	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001261646	SCV001524665	pathogenic	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	2020-06-03	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV001261646	SCV002014503	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	RCV001261646	SCV002041537	likely pathogenic	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	2021-11-16	criteria provided, single submitter	clinical testing	Variant summary: PTS c.238A>G (p.Met80Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251406 control chromosomes. c.238A>G has been reported in the literature as a homozygous genotype and as a founder variant in multiple well phenotyped individuals of Saudi Arabian ancestry affected with 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency (example, Alfadhel_2016, Almannai_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic (n=2). Based on the evidence outlined above, awaiting additional functional evidence and compound heterozygous genotypes among affected individuals, the variant was classified as likely pathogenic.
Invitae	RCV001261646	SCV004294937	pathogenic	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	2022-12-23	criteria provided, single submitter	clinical testing	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 tolerated. ClinVar contains an entry for this variant (Variation ID: 372484). This missense change has been observed in individual(s) with 6-pyruvoyl-tetrahydropterin synthase deficiency (PMID: 27629047, 30926181). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 80 of the PTS protein (p.Met80Val). For these reasons, this variant has been classified as Pathogenic.