ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.618C>A (p.Tyr206Ter) (rs62517201)

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
Counsyl RCV000672692 SCV000797826 pathogenic Phenylketonuria 2018-02-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000672692 SCV000919907 pathogenic Phenylketonuria 2017-09-08 criteria provided, single submitter clinical testing Variant summary: The PAH c.618C>A (p.Tyr206X) variant results in a premature termination codon, predicted to cause a truncated or absent PAH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.727C>T, p.Arg243X; c.1055delG, p.Gly352fsX48; c.1089delG, p.Lys363fsX37). One in silico tool predicts a damaging outcome for this variant. One functional study confirmed that the variant leads to a nonsense mutation that caused significant reduction in mutant transcript levels possibly through activation of nonsense mediated decay (Bashyam 2014). This variant was found in 1/121330 control chromosomes at a frequency of 0.00082%, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.79057%). The variant was reported in the literature in multiple patients with PKU (Song 2006, Bashyam 2014, Li 2015, Acosta 2001). Taken together, this variant is classified as pathogenic.
Invitae RCV000672692 SCV000946663 pathogenic Phenylketonuria 2018-10-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr206*) in the PAH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs62517201, ExAC 0.01%). This variant has been observed to be homozygous or in combination with another PAH variant in individuals affected with phenylketonuria (PMID: 16256386, 24130151, 27121329). ClinVar contains an entry for this variant (Variation ID: 556660). Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic.

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.