ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.612T>G (p.Tyr204Ter) (rs62514928)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000686246 SCV001370844 pathogenic Phenylketonuria 2020-05-08 reviewed by expert panel curation The c.612T>G (p.Tyr204Ter) variant in PAH is a null variant (nonsense variant) in exon 6 of 13 in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is present at extremely low frequency in ethnically diverse control databases, with gnomAD AF 0.00000398 (<0.002, the PAH-specific cutoff) (PM2). It has been reported as a heterozygous variant in at least four PKU cases, with known pathogenic variants in at least two cases (PM3_Strong): with a Sicilian PKU case with BH4 deficiency excluded (PMID: 8268925) (PP4_Moderate); in a German PKU case (PMID: 10394930); in one Spanish case with the pathogenic (per PAH VCEP) p.R176L variant (PMID: 10234516); and in one family (2 affected siblings) and 2 additional mild PKU patients with the pathogenic (per PAH VCEP) p.R68S variant (PMID: 23514811). It has also been reported Pathogenic by three labs in ClinVar (variation ID 102758). Classification: Pathogenic Supporting criteria: PVS1, PM2; PM3_Strong; PP4_Moderate
GeneDx RCV000089008 SCV000490680 pathogenic not provided 2016-03-29 criteria provided, single submitter clinical testing The Y204X variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. The Y204X nonsense variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Patients who are homozygous for Y204X are reported to have classic PKU and are not responsive to BH4 therapy (Guldberg et al., 1993; BIOPKU database). Therefore, we interpret Y204X to be a pathogenic variant.
Invitae RCV000686246 SCV000813756 pathogenic Phenylketonuria 2019-10-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr204*) in the PAH gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported as homozygous and/or in combination with another PAH variant in several individuals affected with phenylketonuria and hyperphenylalaninemia (PMID: 8268925, 23764561, 27121329, 27264808). ClinVar contains an entry for this variant (Variation ID: 102758). Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000686246 SCV001361331 pathogenic Phenylketonuria 2019-11-22 criteria provided, single submitter clinical testing Variant summary: PAH c.612T>G (p.Tyr204X) 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 allele was found at a frequency of 4e-06 in 251338 control chromosomes (gnomAD). c.612T>G has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria)(Aldamiz-Echevarria_2016, Sarkissian_2011). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submissions (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089008 SCV000119612 not provided not provided no assertion provided not provided

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