ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1199+1G>A (rs62509015)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000632882 SCV000754083 pathogenic Phenylketonuria 2017-10-12 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 11 of the PAH gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with phenylketonuria (PMID: 9634518). ClinVar contains an entry for this variant (Variation ID: 102556). 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. A different variant affecting this nucleotide (c.1199+1G>C) has been determined to be pathogenic (PMID: 20187763 , 22763404 , 23856132 , 24301756, 26351554, 26413448). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000632882 SCV000792852 likely pathogenic Phenylketonuria 2017-07-18 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088790 SCV000119377 not provided not provided no assertion provided not provided

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