Classification of a PTS gene variant, c.۴۰۰G>A (p. E۱۳۴K), based on ACMG-AMP criteria

Backgrounds: Defects in the enzymes involved in the BH۴ de novo synthesis or its recyclingpathway may lead to hyperphenylalaninemia (HPA). PTPS is one of the enzymes participated inthe BH۴ de novo synthesis and encodes by PTS gene. To date, about ۲۰۰ PTS gene variants havebeen identified and recorded in BioPKU database (http://www.biopku.org/home/pnddb.asp). Theaim of this study was to predict the pathogenicity of a variant recently reported in an Iranianpatient with PTPS deficiency, c.۴۰۰G>A (p. E۱۳۴K), and classify it based on ACMG-AMPguidelines.Materials and Methods: Ten predictive tools including: CADD, Mutation Taster, Polyphen-۲,I-Mutant disease, PROVEAN, SIFT, SNPs&GO, FATHMM-XF, PhD-SNPg, and PANTHERPSEP, were used. In addition, a literature search was performed in multiple online databases toassign the ACMG-AMP criteria related to c.۴۰۰G>A (p. E۱۳۴K) variant.Results: c.۴۰۰G>A (p. E۱۳۴K) variant showed a deleterious effect in all ten predictive tools.Therefore, we applied PP۳ criterion (defined as: multiple lines of computational evidencesupport a deleterious effect) for this variant. Three other criteria including PM۳_strong (detectedin trans with a pathogenic variant), PM۲ (absent/rare in controls), and PP۴ (patient’s phenotypeor family history is highly specific for a disease with a single genetic etiology) were assigned.Based on these observations, c.۴۰۰G>A (p. E۱۳۴K) was classified as a likely pathogenic variant.Conclusion: Our findings in this study on the likely pathogenic nature of c.۴۰۰G>A (p. E۱۳۴K)will be a good reference for physicians who advise couples carrying this variant.

Keywords:

PTS , ACMG-AMP , hyperphenylalaninemia