Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001375892 | SCV001572851 | likely pathogenic | Phenylketonuria | 2020-08-28 | reviewed by expert panel | curation | The c.-4165_-407del3759 deletion in PAH has been reported in 3 unrelated individuals/families with PAH deficiency where it was designated as -4173_-407del. (PMID: 11935335). The -4173_-407del nomenclature was based on the translation initiation site, and corresponds to c.-4165_-407del3759 (based on transcription initiation site). This deletion is absent from gnomAD genomes with good coverage. This variant was detected with pathogenic variants: p.R408Q in 2 unrelated patients; p.E286K in 2 patients (pathogenic by PAH VCEP); and p.E76G in 1 patient (PMID: 24401910). Functional evidence suggests that it diminishes PAH gene expression (retained only 1% of the wild-type CAT activity, PMID: 11935335). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3_strong, PS3_supporting. |
OMIM | RCV000000670 | SCV000020820 | pathogenic | Hyperphenylalaninemia | 2002-03-01 | no assertion criteria provided | literature only |