ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1200-8G>A (rs62507261)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000525956 SCV001146703 likely pathogenic Phenylketonuria 2019-09-29 reviewed by expert panel curation The c.1200-8G>A variant in PAH has been reported in multiple patients with PAH deficiency. BH4 deficiency excluded (PMID: 9391881, 23062575). This variant has extremely low frequency in gnomAD (MAF=0.00001) (PM2). This variant was detected with known pathogenic variants IVS10-11G>A, p.A403V (PM3). Computational evidence supports a splicing effect (HSF and MaxEnt). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3.
Invitae RCV000525956 SCV000629179 likely pathogenic Phenylketonuria 2017-06-28 criteria provided, single submitter clinical testing This sequence change falls in intron 11 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with classical PKU (PMID: 9391881). ClinVar contains an entry for this variant (Variation ID: 102565). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare intronic change with uncertain impact on protein function that has been reported in individuals with classical PKU. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088799 SCV000119387 not provided not provided no assertion provided not provided
Counsyl RCV000525956 SCV000794779 likely pathogenic Phenylketonuria 2019-02-26 no assertion criteria provided clinical testing

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