ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.824C>G (p.Pro275Arg) (rs62508715)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000672381 SCV000886555 likely pathogenic Phenylketonuria 2018-12-09 reviewed by expert panel curation The c.824C>G (p.Pro275Arg) variant in PAH is absent from population databases and predicted deleterious by multiple in silico algorithms. It is in the same codon as two previously reported likely pathogenic variants (p.Pro275Ser and p.Pro275Leu). It has been identified in trans with a pathogenic variant (PMID: 23514811), and a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine in that patient. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PM5, PP3.
Counsyl RCV000672381 SCV000797480 likely pathogenic Phenylketonuria 2018-01-26 criteria provided, single submitter clinical testing
Invitae RCV000672381 SCV000932925 pathogenic Phenylketonuria 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 275 of the PAH protein (p.Pro275Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another PAH variant in several individuals affected with phenylketonuria (PMID: 15464430, 25882749, 27121329). ClinVar contains an entry for this variant (Variation ID: 102854). 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. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089115 SCV000119722 not provided not provided no assertion provided not provided

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