ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.912+3A>C

dbSNP: rs281865450
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000106374 SCV001250538 uncertain significance Phenylketonuria 2019-11-08 reviewed by expert panel curation The c.912+3A>C variant in PAH has not been reported in the medical literature to the best of our knowledge. This variant is absent from gnomAD and the ESP population databases. This is an intronic variant in a highly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by reducing (~30%) the canonical donor splice site. Given the absence of clinical information and mRNA functional studies, the significance of the c.912+3A>C variant can not be determined with certainty. PAH-specific ACMG/AMP criteria applied: PP3, PM2.
Labcorp Genetics (formerly Invitae), Labcorp RCV000106374 SCV004375513 likely pathogenic Phenylketonuria 2023-04-09 criteria provided, single submitter clinical testing This sequence change falls in intron 8 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 32668217; Invitae; BIOPKU http://www.biopku.org). ClinVar contains an entry for this variant (Variation ID: 120293). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Inserm U 954, Faculté de Médecine de Nancy RCV000106374 SCV000143874 probable-pathogenic Phenylketonuria no assertion criteria provided not provided Converted during submission to Likely pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.