Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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. |
Gene |
RCV000186076 | SCV000239097 | pathogenic | not provided | 2022-03-06 | criteria provided, single submitter | clinical testing | Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Previously reported in multiple unrelated families with phenylketonuria (Shirzadeh et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32668217, 30159852) |
Invitae | RCV000984289 | SCV001383680 | pathogenic | Phenylketonuria | 2023-12-12 | 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, gnomAD 0.01%). Disruption of the initiator codon has been observed in individuals with hyperphenylalaninemia (PMID: 2574002, 10679941, 24941924, 26666653; Invitae). ClinVar contains an entry for this variant (Variation ID: 203873). For these reasons, this variant has been classified as Pathogenic. |
Fulgent Genetics, |
RCV000984289 | SCV002811022 | pathogenic | Phenylketonuria | 2021-12-11 | criteria provided, single submitter | clinical testing | |
Counsyl | RCV000984289 | SCV001132447 | likely pathogenic | Phenylketonuria | 2014-07-02 | no assertion criteria provided | clinical testing | |
Natera, |
RCV000984289 | SCV002088682 | pathogenic | Phenylketonuria | 2021-02-27 | no assertion criteria provided | clinical testing |