ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1A>T (p.Met1Leu)

dbSNP: rs62514891
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000993611 SCV001146719 pathogenic Phenylketonuria 2019-07-07 reviewed by expert panel curation The PAH:p.M1L variant is a predicted start-lost variant in the canonical transcript of PAH (ENST00000553106); There are no other PAH RefSeq 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 was reported in trans with the pathogenic variant p.Arg241His (PM3) in 1 Mexican proband with mild PKU (PMID: 24941924; PP4). It is absent from control databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PVS1.
Labcorp Genetics (formerly Invitae), Labcorp RCV000993611 SCV004296196 pathogenic Phenylketonuria 2023-08-29 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that disruption of the initiator codon affects PAH function (PMID: 1301201). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 102626). Disruption of the initiator codon has been observed in individual(s) with clinical features of PAH-related conditions (PMID: 2574002, 26666653; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the PAH mRNA. The next in-frame methionine is located at codon 180.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088869 SCV000119465 not provided not provided no assertion provided not provided

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