ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1316-1G>A (rs1592944816)

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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 RCV000851536 SCV001370881 pathogenic Phenylketonuria 2020-06-01 reviewed by expert panel curation The c.1316-1G>A variant in PAH is a null variant (canonical +/- 1 or 2 splice sites) in a gene where LOF is a known mechanism of disease. It is predicted to result in skipping of coding exon 13, which is a key domain of the enzyme (PVS1_Strong). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been previously reported in seven Ugyur probands (PMID: 31355225): three homozygotes with mild PKU; one compound heterozygote with classic PKU in trans with the p.R413P variant (Pathogenic per ClinGen PAH working group); one compound heterozygote with classic PKU in trans with the p.R243Q variant (Pathogenic per ClinGen PAH working group); one compound heterozygote with mild PKU in trans with the p.A300S variant (Pathogenic per ClinGen PAH working group); and one compound heterozygote with mild PKU in trans with the p.E182K (Likely Pathogenic per ClinGen PAH working group) variant (PM3_VeryStrong). (In all cases, phase was confirmed by parental testing.) In all cases, BH4 deficiency was formally excluded by urinary pterin analysis (PP4_Moderate). It is reported pathogenic in Clinvar (ID 625286) by one lab, for PKU; no further information is given.
The Molecular Genetic Diagnosis Center, Children’s Hospital of Fudan University RCV000851536 SCV000924698 pathogenic Phenylketonuria 2019-03-08 no assertion criteria provided clinical testing

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