ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.556del (p.Thr186fs) (rs62507328)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000586383 SCV001448303 pathogenic Phenylketonuria 2020-10-15 reviewed by expert panel curation This c.556del (p.Thr186fs) variant in PAH has been observed in two patients with non-PKU hyperphenylalaninemia, with pathogenic variant p.Arg408Trp, phase unknown (PMID: 23357515). This variant is absent from controls in population databases. This is a predicted null frameshift variant in exon 6 out of 13 coding exons. The variant is predicted to undergo nonsense mediated mRNA decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_Supporting, and PP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586383 SCV000696456 likely pathogenic Phenylketonuria 2017-08-04 criteria provided, single submitter clinical testing Variant summary: The PAH c.556delA (p.Thr186Hisfs) 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. The variant of interest has not been found in a large, broad control population, ExAC in 121184 control chromosomes. This variant was found in two compound heterozygotes with hyperphenylalaninemia (Reblova_Clinica Chimica Acta_2013). The variant of interest has been cited by a clinical diagnostic laboratory and reputable database, however, classifications were not provided. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as "likely pathogenic."
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088982 SCV000119586 not provided not provided no assertion provided not provided
Counsyl RCV000586383 SCV000797601 likely pathogenic Phenylketonuria 2018-02-01 no assertion criteria provided clinical testing

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