ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1240T>C (p.Tyr414His) (rs281865437)

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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 RCV000106346 SCV001250536 uncertain significance Phenylketonuria 2019-05-05 reviewed by expert panel curation The c.1240T>C (p.Tyr414His) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 125859); the collection method is stated as "literature only" and no further information is provided. To our knowledge, as of 4/29/19, it has not been reported in the published literature. The variant results in the substitution of a highly conserved Tyrosine residue with Histidine, a physiochemically distinct amino acid (nonpolar versus basic side chains), and the amino acid substitution is predicted damaging by multiple lines of computational evidence e.g., Predicted deleterious in SIFT, Polyphen2, Mutation Taster. REVEL= 0.969) (PP3). It is present at extremely low frequency in control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP: the highest MAF reported is 0.00001, in the gnomAD/ExAC Non-Finnish European subpopulation, which falls below the 0.0002 allele frequency cutoff for PAH variants (PM2). Another missense variant at this site, p.Tyr414Cys, has been previously reported Pathogenic, including by the ClinGen PAH working group (see ClinVar variant ID 593) (PM5).
Inserm U 954, Faculté de Médecine de Nancy RCV000106346 SCV000143845 probable-pathogenic Phenylketonuria no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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