ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.969+6T>A (rs62517196)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000664529 SCV001250553 uncertain significance Phenylketonuria 2020-01-26 reviewed by expert panel curation The c.969+6T>A variant in PAH has been reported in 2 patients with benign HPA (BH4 deficiency excluded) (PP4_Moderate; PMID: 8659548, 24941924). It was detected with known pathogenic variant c.1162G>A, (p.Val388Met) (PMID: 24941924). This variant has a frequency of 0.00033 in Latino population, which is higher than our PM2 cut-off (0.0002). A deleterious effect is predicted in HSF and TraP. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3, PP3.
Counsyl RCV000664529 SCV000788506 uncertain significance Phenylketonuria 2017-05-12 criteria provided, single submitter clinical testing
Invitae RCV000664529 SCV000828714 pathogenic Phenylketonuria 2019-09-19 criteria provided, single submitter clinical testing This sequence change falls in intron 9 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs62517196, ExAC 0.03%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in individuals with elevated plasma phenylalanine, findings that are highly specific for hyperphenylalaninemia (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has been reported in combination with other PAH variants in individuals affected with PAH-related disease (PMID: 24941924). ClinVar contains an entry for this variant (Variation ID: 102916). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089182 SCV000119797 not provided not provided no assertion provided not provided

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.