ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1068C>A (p.Tyr356Ter) (rs62516095)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000150078 SCV000852132 pathogenic Phenylketonuria 2018-08-13 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PM2: gnomAD MAF 0.00017; PP4_Moderate: Detected in PKU patients (PMID:25894915); PM3_Strong: in trans with p.W326X (Pathogenic), and IVS4-1G>A (Pathogenic). (PMID:25894915). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4_Moderate, PM3_Strong).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078501 SCV000110357 pathogenic not provided 2013-11-11 criteria provided, single submitter clinical testing
Counsyl RCV000150078 SCV000220711 pathogenic Phenylketonuria 2014-09-18 criteria provided, single submitter literature only
GeneDx RCV000078501 SCV000239085 pathogenic not provided 2017-05-05 criteria provided, single submitter clinical testing The Y356X nonsense variant in the PAH gene has been reported as a pathogenic variant in the PAHConsortium database. The Y356X variant has been previously reported in individuals withphenylketonuria (PKU) (Liang et al., 2014; Liu et al., 2015; Chen et al., 2015; Jeannesson-Thivisol etal., 2015). Functional analysis found that Y356X is associated with significantly reduced enzymeactivity compared to wild type (Zurfluh et al., 2008). It has been reported as non-responsive totetrahydrobiopterin (BH4) therapy (Zurfluh et al., 2008; Jeannesson-Thivisol et al., 2015). TheY356X variant is predicted to cause loss of normal protein function either through protein truncationor nonsense-mediated mRNA decay.
Invitae RCV000150078 SCV000814397 pathogenic Phenylketonuria 2019-07-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr356*) in the PAH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs62516095, ExAC 0.01%). This variant has been observed in combination with other PAH variants in individuals affected with PAH deficiency-related disease (PMID: 7915167, 27264808). ClinVar contains an entry for this variant (Variation ID: 92729). A different variant (c.1068C>G) giving rise to the same protein effect observed here (p.Tyr356*) has been reported in individuals affected with PAH deficiency (PMID: 9860305, 10471838, 24301756, 26322415, 26600521, 26666653). Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000150078 SCV001163715 pathogenic Phenylketonuria criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000150078 SCV001363417 pathogenic Phenylketonuria 2019-02-04 criteria provided, single submitter clinical testing Variant summary: PAH c.1068C>A (p.Tyr356X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 245780 control chromosomes (gnomAD). c.1068C>A has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Tao_2015, Eiken_1996). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078501 SCV000119328 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.