ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.499A>T (p.Asn167Tyr)

gnomAD frequency: 0.00001  dbSNP: rs1210056131
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV001375887 SCV001572843 uncertain significance Phenylketonuria 2020-12-07 reviewed by expert panel curation This c.499A>T (p.Asn167Tyr) variant in PAH was reported in 1 patient with PAH deficiency referred to as non-PKU HPA (120 - 600uMol/L Phe), it was detected with pathogenic variant p.Arg408Trp (PMID: 23357515). Computational evidence for this variant is conflicting; predicted to be damaging (SIFT), disease-causing (MutationTaster) and benign (PolyPhen2). This variant was found at an extremely low frequency in gnomAD (MAF=0.00005723). Functional studies have been reported with no major impact on enzyme activity as compared to wild type (PMID: 31208052). In summary, this variant meets criteria to be classified as a variant of uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3 supporting, PP4.
Labcorp Genetics (formerly Invitae), Labcorp RCV001375887 SCV003441157 uncertain significance Phenylketonuria 2023-01-07 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 23357515). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 167 of the PAH protein (p.Asn167Tyr). ClinVar contains an entry for this variant (Variation ID: 1065373). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PAH function (PMID: 31208052). 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 not expected to disrupt PAH protein function.

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