ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.461A>T (p.Tyr154Phe)

dbSNP: rs1565853526
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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 RCV001093514 SCV001250546 likely pathogenic Phenylketonuria 2020-01-26 reviewed by expert panel curation The c.461A>T (p.Tyr154Phe) variant in PAH has been reported in 3 individuals with PKU (BH4 deficiency excluded). (PMID: 24368688, 31332730). This variant is absent in population databases (PM2). This variant was detected with pathogenic variant c.1315+1G>A (IVS12+1G>A) (PMID: 24368688). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PP3.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759178 SCV000888348 likely pathogenic not provided 2018-01-14 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001093514 SCV004296181 pathogenic Phenylketonuria 2023-10-08 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 154 of the PAH protein (p.Tyr154Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 24368688, 31332730). ClinVar contains an entry for this variant (Variation ID: 619705). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function. This variant disrupts the p.Tyr154 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17397052, 24767306, 25725806, 26892377, 30199612). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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