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 2019-08-21 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect, resulting in very low residual phenylalanine hydroxylase activity compared to wild-type (Liang et al., 2014; Zurflh et al., 2008); Classified as not responsive to tetrahydrobiopterin (BH4) therapy (Zurflh et al., 2008); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30747360, 25525159, 8406445, 10471838, 24401910, 17935162, 31980526)
Invitae RCV000000626 SCV000629171 pathogenic Phenylketonuria 2020-04-28 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000000626 SCV001363419 pathogenic Phenylketonuria 2020-07-24 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. 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. At least one publication reported 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). The variant allele was found at a frequency of 2e-05 in 251004 control chromosomes. c.1068C>G has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria; e.g. Ellingsen_1999, Eiken_1996, Okano_1998, Liang_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that the variant impairs enzyme activity (e.g. Liang_2014). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited 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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