ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.580_581del (p.Leu194fs)

dbSNP: rs62508587
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000169180 SCV001448677 pathogenic Phenylketonuria 2020-10-30 reviewed by expert panel curation The c.578_579del PAH variant has been identified in at least one patient with classic PKU (PMID: 26666653). The patient was compound heterozygous with the pathogenic variant Leu348Val (ClinVar 92727). This variant is absent from 1000G, ESP, and gnomAD databases. This variant leads to the frameshift Leu194GlufsTer5, creating a stop codon in exon 6 of 13 which is predicted to cause NMD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PP4, PM2, PM3_supporting.
Counsyl RCV000169180 SCV000220417 likely pathogenic Phenylketonuria 2014-06-16 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169180 SCV002511464 pathogenic Phenylketonuria 2022-04-22 criteria provided, single submitter clinical testing Variant summary: PAH c.580_581delCT (p.Leu194GlufsX5) 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 251338 control chromosomes (gnomAD). c.580_581delCT has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria, e.g. Aulehla-Scholz_2003, Sarkissian_2012, Jeannesson-Thivisol_2015). 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 ClinVar submitter (an expert panel) has assessed this variant since 2014: the variant was classified as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000169180 SCV005053834 pathogenic Phenylketonuria 2024-01-24 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088990 SCV000119594 not provided not provided no assertion provided not provided

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