ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1068C>G (p.Tyr356Ter) (rs62516095)

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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 RCV000000626 SCV000852156 pathogenic Phenylketonuria 2018-08-07 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PM2: ExAC MAF:0.00006.; PP4_Moderate: seen in classic and mild PKU patients. BH4 deficiency excluded.. 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_Moderate).
Counsyl RCV000000626 SCV000220965 likely pathogenic Phenylketonuria 2014-12-16 criteria provided, single submitter literature only
GeneDx RCV000088745 SCV000516832 pathogenic not provided 2015-04-22 criteria provided, single submitter clinical testing The Y356X variant in the PAH gene has been reported previously in associationwith phenylketonuria (PKU) (Liang et al., 2014; Zurfluh et al., 2008). The Y356X variant is predicted tocause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decayand is expected to be associated with a classic phenylketonuria phenotype as expression studies found thatthis variant is associated with very low residual phenylalanine hydroxylase activity compared to wild-type(Liang et al., 2014; Zurfluh et al., 2008). The Y356X variant was found to not be responsive totetrahydrobiopterin (BH4) therapy (Zurfluh et al., 2008). Therefore, we interpret this variant as pathogenic.
Invitae RCV000000626 SCV000629171 pathogenic Phenylketonuria 2019-12-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 356 (p.Tyr356*) of the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic. This particular variant has been reported in several individuals affected with phenylketonuria and hyperphenylalaninemia, being described as a common cause of the disease in Asia. In the homozygous state it has been associated with the classical form of phenylketonuria (PMID: 9860305, 10471838, 24301756, 26322415, 26600521, 26666653). Experimental studies have shown that this variant also leads to out-of-frame skipping of exon 11 of the PAH gene (PMID: 7915167, 10471838). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000000626 SCV001363419 pathogenic Phenylketonuria 2019-03-11 criteria provided, single submitter clinical testing Variant summary: PAH c.1068C>G (p.Tyr356X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant is also located close to a canonical splice site in exon 11, and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Computational tools predict that the variant could weaken a 3' acceptor site. This prediction has been confirmed by at least one publication that has demonstrated that the variant caused the complete lack of the full-length transcript in lymphocytes isolated from a homozygous patient, while resulting in two shorter fragments: one transcript with an out of frame skipping of exon 11 (~70%), and a second transcript (~30%) with an in frame deletion of exon 8-11 (that is predicted to result in the deletion of amino acids 282-400) (Ellingsen 1999). Another in vitro study, examining the protein level effects of this variant, using an (intronless) cDNA construct, demonstrated that the variant resulted in the lack of enzyme activity (Liang 2014); however in light of the strong spliceogenic effect, this finding might not reflect the overall consequence of the variant. The variant allele was found at a frequency of 1.8e-05 in 276720 control chromosomes (gnomAD) and has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria; PKU) (e.g. Ellingsen 1999, Eiken 1996, Okano 1998, Liang 2014), where a homozygous patient was described with the classic phenotype of PKU (Ellingsen 1999). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000000626 SCV000020776 pathogenic Phenylketonuria 1989-11-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088745 SCV000119329 not provided not provided no assertion provided not provided

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