ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.3G>C (p.Met1Ile) (rs62514893)

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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 RCV000709702 SCV001146724 likely pathogenic Phenylketonuria 2019-07-07 reviewed by expert panel curation The c.3G>C (p.Met1Ile) variant in PAH is a null variant (start loss) where LOF is a known mechanism of disease. There are no known alternative start codons in other transcripts. The next in-frame Met is at amino acid 180 in exon 6. There are 49 pathogenic variants in ClinVar upstream of aa 180. The p.Met1Val variant has <3% enzyme activity as compared to wild type (PMID: 9450897), confirming start loss variants lead to loss of function of the PAH enzyme without re-initiation. This variant is absent in population databases (PM2). This variant has not been reported in an affected individual in the literature to our knowledge. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PVS1.
Clinical Laboratory,Xuzhou Maternity and Child Health Care Hospital RCV000709702 SCV000839873 pathogenic Phenylketonuria 2018-06-26 no assertion criteria provided case-control

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