ClinVar Miner

Submissions for variant NM_001354304.2(PAH):c.-95-4071_-95-313del

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel 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

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