Submissions for variant NM_000277.3(PAH):c.461A>G (p.Tyr154Cys)

dbSNP: rs1565853526

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001543644	SCV001762320	likely pathogenic	Phenylketonuria	2021-01-15	reviewed by expert panel	curation	This c.461A>G (p.Tyr154Cys) variant in PAH was reported in trans with pathogenic variant c.728G>A (p. Arg243Gln) in a patient with PAH deficiency (>120 μmol/L Phe) (PMID: 19915519, 23932990, 28754886). Computational evidence for this missense variant is predicted to be damaging (SIFT), probably damaging (PolyPhen2), and disease-causing (MutationTaster). This variant is absent from population databases ExAC, gnomAD, 1000 Genomes, ESP. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001543644	SCV002260398	likely pathogenic	Phenylketonuria	2021-05-20	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine with cysteine at codon 154 of the PAH protein (p.Tyr154Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 32668217). 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: 16256386, 32668217). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.