ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.974A>G (p.Tyr325Cys) (rs62508578)

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Total submissions: 5
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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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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 likely pathogenic Phenylketonuria 2019-05-29 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 325 of the PAH protein (p.Tyr325Cys). 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 on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with classical PKU (PMID: 10679941). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 92756). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078541 SCV000119802 not provided not provided no assertion provided not provided

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