ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.895T>C (p.Phe299Leu) (rs796064504)

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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 RCV000190378 SCV001250537 uncertain significance Phenylketonuria 2019-06-09 reviewed by expert panel curation The c.895T>C (p.Phe299Leu) variant in PAH is reported as Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 208182); no further information is provided. At the time of review (5/25/19), the variant does not appear to be reported in the published literature and/or in the BioPKU database. The variant results in the substitution of a highly conserved Phenylalanine residue with Leucine; the amino acid substitution is predicted damaging by multiple lines of computational evidence e.g., predicted deleterious in SIFT, Polyphen2, Mutation Taster; REVEL= 0.96) (PP3). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). Another missense variant at this site, p.Phe299Cys, has been previously reported Pathogenic/Likely Pathogenic by seven submitters in ClinVar (variant ID 613), where it was noted to be a recurrent allele among Norwegian PKU patients and have in-vitro data supporting that it impaired protein function. Another missense variant at this site, Phe299Ser, has also been reported in the BioPKU database (PAH0800). These reports of those variants support use of PM5.
Inserm U 954, Faculté de Médecine de Nancy RCV000190378 SCV000243912 probable-pathogenic Phenylketonuria no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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