ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.498C>G (p.Tyr166Ter)

dbSNP: rs199475645
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000410899 SCV002540165 pathogenic Phenylketonuria 2022-01-22 reviewed by expert panel curation The c.498C>G (p.Tyr166Ter) variant in PAH is a nonsense variant in exon 5 of 13 in PAH, predicted to undergo nonsense mediated decay. It has been reported in multiple individuals, including in homozygosity in a classic PKU patient in the Uyger population. (PM3, PP4, PMID:31355225). This variant is absent from ExAC/gnomAD, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_supporting, PP4_moderate.
Counsyl RCV000410899 SCV000486935 pathogenic Phenylketonuria 2016-09-07 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000410899 SCV000932582 pathogenic Phenylketonuria 2024-02-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr166*) in 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 (PMID: 1301187, 9634518). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hyperphenylalaninemia and/or phenylketonuria (PMID: 16256386, 28754886, 29176022). ClinVar contains an entry for this variant (Variation ID: 371373). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000410899 SCV002103437 pathogenic Phenylketonuria 2022-02-07 criteria provided, single submitter clinical testing Variant summary: PAH c.498C>G (p.Tyr166X) 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 was absent in 251362 control chromosomes (gnomAD). The variant c.498C>G has been reported in the literature in several homozygous and compound heterozygous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Zhu_2013, Tao_2015, Li_2018, Xiao_2021). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000410899 SCV004209626 pathogenic Phenylketonuria 2024-02-28 criteria provided, single submitter clinical testing
Natera, Inc. RCV000410899 SCV002088665 pathogenic Phenylketonuria 2020-07-05 no assertion criteria provided clinical testing

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