ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.2T>C (p.Met1Thr) (rs62508575)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000984289 SCV001146696 likely pathogenic Phenylketonuria 2019-07-07 reviewed by expert panel curation c.2T>C (p.Met1Thr) is a null PAH 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 has an extremely low frequency in ExAC, ESP, gnomAD. However, it has not been reported 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: PVS1, PM2.
GeneDx RCV000186076 SCV000239097 pathogenic not provided 2016-06-22 criteria provided, single submitter clinical testing The c.2 T>C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The c.2 T>C variants alters the initiator Methionine codon, and the resultant protein would be described as p.Met1?" using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met. Other variants affecting the initiator Methionine codon (c.2 T>G, c.3 G>A, c.1 A>G) have also been reported as severe PAH variants associated with a classic phenylketonuria phenotype (Hennermann et al., 2000; Eiken et al., 1992; John et al., 1989). Therefore, we interpret c.2 T>C as a pathogenic variant"
Invitae RCV000984289 SCV001383680 pathogenic Phenylketonuria 2019-06-07 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the PAH mRNA. The next in-frame methionine is located at codon 180. This variant is present in population databases (rs62508575, ExAC 0.01%). Disruption of the initiator codon has been observed in several individuals affected with hyperphenylalaninemia (PMID: 10679941, 24941924, 26666653, 2574002, Invitae). ClinVar contains an entry for this variant (Variation ID: 203873). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000984289 SCV001132447 likely pathogenic Phenylketonuria 2014-07-02 no assertion criteria provided clinical testing

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