ClinVar Miner

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

dbSNP: rs1057517810
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Total submissions: 5
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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.

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