ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1161C>A (p.Tyr387Ter)

dbSNP: rs149595475
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV001194128 SCV001370831 pathogenic Phenylketonuria 2020-05-08 reviewed by expert panel curation Variant c.1161C>A (p.Tyr387Ter) in PAH was documented 2 times in European patients with classic phenylketonuria (PMID: 16601866, 23764561)(PP4-moderate). This is a nonsense variant in exon 11 out of 13 coding exons, predicted to undergo nonsense mediated mRNA decay, as it is not located in the 3'-most exon or the 3'-most 50 bp of the penultimate exon. The exon is present in biologically-relevant transcripts (PVS1). This variant was detected in trans with pathogenic variant p.P281L (PMID:16601866, 23764561) (PM3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied:PVS1, PM3, PP4-Moderate.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194128 SCV001363422 pathogenic Phenylketonuria 2019-05-10 criteria provided, single submitter clinical testing Variant summary: PAH c.1161C>A (p.Tyr387X) 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 251252 control chromosomes (gnomAD). The variant, c.1161C>A, has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Leuzzi_2006, Reblova_2013, Polak_2013). These data indicate that the variant may be associated with disease. One publication, Polak_2013, reports in vitro PAH activity of this variant was <10% of normal activity. 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.

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