ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.535T>C (p.Tyr179His)

dbSNP: rs199475671
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV001778707 SCV002818503 likely pathogenic Phenylketonuria 2022-12-09 reviewed by expert panel curation The c.535T>C (p.Tyr179His) variant in PAH has been reported in multiple individuals with PKU, including in patients with classic PKU in whom BH4 deficiency has been excluded (PMID: 29997390, PMID: 16256386, PMID: 20920871, PMID: 32668217, PMID: 30389586). p.Tyr179His has been detected with multiple variants classified as likely pathogenic or pathogenic by PAH VCEP, including p.Arg176*, c.1066-11G>A, c.1199+1G>C, p.Ala403Val, p.Ile406Met, p.Arg408Trp, p.Val230Ile (PMID: 32668217). This variant is absent from population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PM2, PP4_Moderate, PP3.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001778707 SCV002014805 pathogenic Phenylketonuria 2021-10-08 criteria provided, single submitter clinical testing Variant summary: PAH c.535T>C (p.Tyr179His) results in a conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251232 control chromosomes (gnomAD). c.535T>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Song_2006, Zare-Karizi_2011, Sarkissian_2012, Shirzadeh_2018). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088979 SCV000119583 not provided not provided no assertion provided not provided

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.