ClinVar Miner

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

dbSNP: rs62507328
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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 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 pathogenic Phenylketonuria 2021-11-07 criteria provided, single submitter clinical testing Variant summary: PAH c.556delA (p.Thr186HisfsX9) 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 251302 control chromosomes. c.556delA has been reported in the literature as a compound heterozygous genotype with other pathogenic PAH alleles in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Reblova_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories and an expert panel (ClinGen PAH Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (Expert panel)/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000586383 SCV002240092 pathogenic Phenylketonuria 2022-08-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr186Hisfs*9) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with phenylketonuria (PMID: 23357515, 32668217). ClinVar contains an entry for this variant (Variation ID: 102733). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000586383 SCV004201334 pathogenic Phenylketonuria 2023-10-25 criteria provided, single submitter clinical testing
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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