ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.648C>G (p.Tyr216Ter) (rs62509013)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000089019 SCV000231508 pathogenic not provided 2014-11-19 criteria provided, single submitter clinical testing
Invitae RCV000179283 SCV000813184 pathogenic Phenylketonuria 2019-11-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr216*) in the PAH gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with phenylketonuria (PMID: 17502162, 26666653). ClinVar contains an entry for this variant (Variation ID: 102769). Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000089019 SCV001167689 pathogenic not provided 2019-03-01 criteria provided, single submitter clinical testing The Y216X variant has been reported in patients with classic phenylketonuria (PKU) including a patient who was homozygous for Y216X and who was not responsive to tetrahydrobiopterin (BH4) therapy (Jeannesson-Thivisol et al. 2015). The Y216X variant is not observed in large population cohorts (Lek et al., 2016). The Y216X variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret this variant as pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000179283 SCV001361065 pathogenic Phenylketonuria 2019-06-06 criteria provided, single submitter clinical testing Variant summary: PAH c.648C>G (p.Tyr216X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251324 control chromosomes (gnomAD). c.648C>G has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Tyfield_1997, Dombrowolski_2007, Sarkissian_2011, Jeannesson-Thivisol_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites 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 RCV000089019 SCV000119624 not provided not provided no assertion provided not provided

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