ClinVar Miner

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

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Total submissions: 13
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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
Invitae RCV000000630 SCV000629220 pathogenic Phenylketonuria 2020-10-08 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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000000630 SCV000803785 likely pathogenic Phenylketonuria 2017-08-16 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000089129 SCV001249177 pathogenic not provided 2019-09-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000000630 SCV001361327 pathogenic Phenylketonuria 2020-12-14 criteria provided, single submitter clinical testing Variant summary: PAH c.842+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.4e-05 in 251272 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (4.4e-05 vs 0.0079), allowing no conclusion about variant significance. c.842+1G>A has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria; Example: Dianzani_1991, Leuzzi_2006, Aldamiz-Echevarria_2016, Li_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other ClinVar submitters (evaluation after 2014) including an expert panel (ClinGen PAH Variant Curation Expert Panel) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Elsea Laboratory,Baylor College of Medicine RCV000000630 SCV001424295 pathogenic Phenylketonuria 2020-04-01 criteria provided, single submitter clinical testing
GeneDx RCV000089129 SCV001820031 pathogenic not provided 2021-01-05 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32668217, 31589614, 30747360, 26666653, 25525159, 23764561, 20188615, 16256386, 24941924, 26589311, 20920871, 1671810, 17935162)
OMIM RCV000000630 SCV000020780 pathogenic Phenylketonuria 1991-03-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089129 SCV000119739 not provided not provided no assertion provided not provided
Natera, Inc. RCV000000630 SCV001453098 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000089129 SCV001929136 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000089129 SCV001960095 likely pathogenic not provided no assertion criteria provided clinical testing

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