ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.442-1G>A (rs62514907)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000000625 SCV000852173 pathogenic Phenylketonuria 2018-08-05 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: Not present in ExAC or 1000 genomes (PMID:9860305); PVS1: Canonical -1 splice site; PP4_Moderate: Reported in a mild PKU patient. BH4 deficiency assessed. (PMID:14681498). 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: (PM2, PVS1, PP4_Moderate).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000088924 SCV000230888 pathogenic not provided 2014-08-08 criteria provided, single submitter clinical testing
GeneDx RCV000088924 SCV000577484 pathogenic not provided 2017-03-28 criteria provided, single submitter clinical testing The c.442-1 G>A pathogenic variant in the PAH gene has previously beenreported in association with both mild and classic PKU (Liang et al., 2014; Wang et al., 1991). Thec.442-1 G>A variant destroys the canonical splice acceptor site in intron 4, and is expected to causeabnormal gene splicing. The c.442-1 G>A variant is not observed in large population cohorts (Lek etal., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). It is unclear whether or notc.442-1 G>A is responsive to BH4 therapy (Zurfluh et al., 2008). In summary, we interpret c.442-1G>A as pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000000625 SCV001361328 pathogenic Phenylketonuria 2019-09-27 criteria provided, single submitter clinical testing Variant summary: PAH c.442-1G>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: Five predict the variant abolishes a 3 acceptor site and creates a new cryptic exonic one. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251264 control chromosomes (gnomAD). c.442-1G>A has been reported in the literature in multiple individuals, including compound heterozygotes and homozygotes, affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Lee_2004, Liang_2014). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function determined the variant to confer null PAH activity in vitro (Liang_2014). Two ClinVar submitters including an expert panel (ClinGen PAH Variant Curation Expert Panel) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000000625 SCV001400309 pathogenic Phenylketonuria 2019-11-18 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 4 of the PAH gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another PAH variant in individuals affected with hyperphenylalaninemia and is considered a founder variant in the Chinese population (PMID: 29499199, 1998345, 24401910). ClinVar contains an entry for this variant (Variation ID: 594). 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 RCV000000625 SCV000020775 pathogenic Phenylketonuria 1991-06-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088924 SCV000119523 not provided not provided no assertion provided not provided

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