ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.842+1G>A (rs5030852)

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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, RCV000000630 SCV000852168 pathogenic Phenylketonuria 2018-08-13 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PVS1: Canonical +1 splice site; PM2: gnomAD MAF 0.00008; PP4: Reported in 3 PKU populations: Slovak, Germany, Italy (PMID:1671810; PMID:10394930; PMID:23764561); PM3: (PMID:20188615; PMID:24941924). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PM2, PP4, PM3).
Counsyl RCV000000630 SCV000221050 likely pathogenic Phenylketonuria 2015-01-16 criteria provided, single submitter literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089129 SCV000119739 not provided not provided no assertion provided not provided
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000000630 SCV000803785 likely pathogenic Phenylketonuria 2017-08-16 criteria provided, single submitter clinical testing
Invitae RCV000000630 SCV000629220 pathogenic Phenylketonuria 2018-11-09 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 of the PAH gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs5030852, ExAC 0.006%). This variant has been reported as homozygous or in combination with another PAH variant in individuals and several families affected with phenylketonuria (PMID: 24941924, 16256386, 20188615, 23764561). This variant is also known as IVS VII-1G>A and IVS7+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 599). 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. 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.
OMIM RCV000000630 SCV000020780 pathogenic Phenylketonuria 1991-03-01 no assertion criteria provided literature only

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