ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1066-1G>T

dbSNP: rs62508684
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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 RCV001093523 SCV001250563 pathogenic Phenylketonuria 2019-10-18 reviewed by expert panel curation This c.1066-1G>T (IVS10-1G>T) variant in PAH was reported in one Chinese patient with PAH deficiency (PMID: 26503515). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant is absent from the population databases ExAC and gnomAD. This variant in the -1 splice acceptor site results in exon skipping. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4_moderate.
Invitae RCV001093523 SCV004294270 pathogenic Phenylketonuria 2023-09-04 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This sequence change affects an acceptor splice site in intron 10 of the PAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with phenylketonuria (PMID: 12655550, 26322415, 26503515). ClinVar contains an entry for this variant (Variation ID: 872842). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.

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