ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.2T>G (p.Met1Arg)

dbSNP: rs62508575
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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 RCV000993612 SCV001146720 pathogenic Phenylketonuria 2019-07-07 reviewed by expert panel curation The PAH:p.M1R variant is a predicted start-lost variant in the canonical transcript of PAH (ENST00000553106). 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. The variant has been previously reported in 2 unrelated probands with classic PKU, in trans with the pathogenic variant p.R408W (PMID: 10679941; PM3); BH4 deficiency was excluded (PP4_Moderate). The variant is sufficiently rare in control databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PM2, PP4_moderate, PVS1.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088893 SCV000119491 not provided not provided no assertion provided not provided

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