ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.974A>G (p.Tyr325Cys)

dbSNP: rs62508578
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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 RCV000150081 SCV001370847 likely pathogenic Phenylketonuria 2020-02-23 reviewed by expert panel curation The c.974A>G (p.Tyr325Cys) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). It was detected with pathogenic/LP variants p.L194P (LP) PMID: 23430918 L348V (P) PMID: 10679941 p.P281L (LP) PMID: 22526846 p.R408W (P) with parental analysis not reported for 1.5 points. This variant has extremely low frequency in gnomAD (MAF=0.00001). Computational evidence supports a 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, PP3.
Eurofins Ntd Llc (ga) RCV000078541 SCV000110397 pathogenic not provided 2012-08-14 criteria provided, single submitter clinical testing
Counsyl RCV000150081 SCV000796739 likely pathogenic Phenylketonuria 2017-12-28 criteria provided, single submitter clinical testing
Invitae RCV000150081 SCV000822786 pathogenic Phenylketonuria 2023-08-17 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 10679941, 32668217; BIOPKU http://www.biopku.org). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 325 of the PAH protein (p.Tyr325Cys). This variant is present in population databases (rs62508578, gnomAD 0.0009%). ClinVar contains an entry for this variant (Variation ID: 92756). 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. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078541 SCV000119802 not provided not provided no assertion provided not provided
Natera, Inc. RCV000150081 SCV002088636 likely pathogenic Phenylketonuria 2020-09-14 no assertion criteria provided clinical testing

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