ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.168+1G>A

dbSNP: rs62514898
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000169163 SCV000886558 pathogenic Phenylketonuria 2018-12-09 reviewed by expert panel curation The c.168+1G>A variant in PAH is at a canonical splice site at intron 3, and is absent in all population databases. It has been identified in trans with a pathogenic variant (Ho, 2014), and as a homozygous variant (PMID: 18294361) in patients with phenylketonuria. Defects in BH4 metabolism were excluded as a cause of elevated phenylalanine in two patients (PMID: 24368688, 8807331). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4_Moderate.
Counsyl RCV000169163 SCV000220391 likely pathogenic Phenylketonuria 2014-06-06 criteria provided, single submitter literature only
Labcorp Genetics (formerly Invitae), Labcorp RCV000169163 SCV001590612 pathogenic Phenylketonuria 2023-04-07 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 102604). Disruption of this splice site has been observed in individual(s) with phenylketonuria (PMID: 8807331, 24368688). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000169163 SCV004201364 pathogenic Phenylketonuria 2023-12-31 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088846 SCV000119441 not provided not provided no assertion provided not provided
Natera, Inc. RCV000169163 SCV002088676 pathogenic Phenylketonuria 2019-12-14 no assertion criteria provided clinical testing

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