ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.58C>T (p.Gln20Ter) (rs199475585)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000169450 SCV001146739 pathogenic Phenylketonuria 2019-02-26 reviewed by expert panel curation Pathogenic: The c.58C>T (p.Gln20Ter) is a null variant reported in one patient with classic PKU phenotype (PVS1, PP4, PMID: 9391881). This variant is absent from population databases, including gnomAD, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4.
Counsyl RCV000169450 SCV000220871 likely pathogenic Phenylketonuria 2014-11-12 criteria provided, single submitter literature only
CeGaT Praxis fuer Humangenetik Tuebingen RCV000088993 SCV001250403 pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000169450 SCV001370580 pathogenic Phenylketonuria 2020-05-25 criteria provided, single submitter clinical testing Variant summary: PAH c.58C>T (p.Gln20X) 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 251430 control chromosomes. c.58C>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Kozak_1997, Guldberg_1998, Quirk_2012, Djordjevic_2013, Polak_2013, Reblova_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory and one expert panel (ClinGen) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000169450 SCV001400667 pathogenic Phenylketonuria 2019-08-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln20*) 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 combination with another PAH variant in individuals affected with classic phenylketonuria (PKU) (PMID: 27121329, 23430547, 23764561, 9391881, 23357515). ClinVar contains an entry for this variant (Variation ID: 102744). Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088993 SCV000119597 not provided not provided no assertion provided not provided

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