ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.504C>A (p.Tyr168Ter)

dbSNP: rs281865455
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000106358 SCV001146734 pathogenic Phenylketonuria 2019-05-26 reviewed by expert panel curation The c.504C>A (p.Tyr168Ter) variant in PAH has been previously reported in one proband with mild hyperphenylalanemia (PMID: 26666653; PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH VCEP, see ClinVar ID 92751) c.898G>T (p.Ala300Ser); however, the phase of the variants was not confirmed via parental testing (PM3_supporting). The sequence change results in a nonsense variant which occurs in exon 5 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4, PM3_supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV000106358 SCV001407822 pathogenic Phenylketonuria 2019-10-15 criteria provided, single submitter clinical testing Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant has been observed in an individual affected with hyperphenylalaninemia (PMID: 26666653). ClinVar contains an entry for this variant (Variation ID: 120277). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr168*) in the PAH gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic.
Inserm U 954, Faculté de Médecine de Nancy RCV000106358 SCV000143857 probable-pathogenic Phenylketonuria no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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