ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.442-2A>C

dbSNP: rs281865448
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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 RCV000106357 SCV001448252 pathogenic Phenylketonuria 2020-07-24 reviewed by expert panel curation The c.442-2A>C variant in PAH is a canonical splice acceptor in which exon skipping disrupts the reading frame and is predicted to undergo nonsense mediated-decay. This variant was documented in 3 patients with classic PKU (PMID 26666653, 18937047, 9048935). It was detected with pathogenic variants c.1042C>G and p.Tyr204Cys (PMID 18937047, 9048935). This variant is absent in population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, and PP4.
Counsyl RCV000106357 SCV000485442 likely pathogenic Phenylketonuria 2015-12-11 criteria provided, single submitter clinical testing
Invitae RCV000106357 SCV002243747 pathogenic Phenylketonuria 2021-03-26 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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. This variant has been observed in individual(s) with phenylketonuria (PMID: 9048935). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 120276). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 4 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).
Inserm U 954, Faculté de Médecine de Nancy RCV000106357 SCV000143856 probable-pathogenic Phenylketonuria no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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