Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000993631 | SCV001146763 | pathogenic | Phenylketonuria | 2019-04-04 | reviewed by expert panel | curation | The c.190_194delCACAT variant in PAH has been previously reported as a single variant, found in trans with the Likely Pathogenic (per internal PAH ClinGen Working Group classification -see PAH0095) p.Ala156Pro variant in a female Chinese proband with classic PKU (PM3) (PMID: 28754886); the authors report that BH4 deficiency was excluded by 'analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes' (PP4_Moderate) (PMID: 28754886). The sequence change results in a nonsense variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4_Moderate, PM3. |