ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1316-2A>C

dbSNP: rs760830761
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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 RCV001199996 SCV001370835 pathogenic Phenylketonuria 2020-05-14 reviewed by expert panel curation Variant c.1316-2A>C in PAH was found in 1 Chinese patient with Phe levels >120 umol/L (PMID: 26322415). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PP4-Moderate). Null variant, canonical -2 splice sites, is in a gene where LOF is a known mechanism of disease. Exon skipping disrupts the reading frame. Altered region is critical to protein function. Not predicted to undergo NMD, because coding exon number is 13 out of 13 coding exons (PVS1-Strong). Variant was found in trans with a pathogenic variant p.R241C (PMID: 26322415). All mutations identified in patients were confirmed by analyzing parental DNA via Sanger automated sequencing (PM3). Variant is absent from controls in gnomAD, PAGE, 1000 Genomes, or ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1-Strong, PM2, PP4-Moderate, PM3.
Baylor Genetics RCV001199996 SCV004209716 pathogenic Phenylketonuria 2022-12-18 criteria provided, single submitter clinical testing

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