Please note this is a beta version of the ClinGen Evidence Repository. This resource is intended to provide access to variant level evidence used and applied by ClinGen Variant Curation Expert Panels in the classification of variants. In this beta version, the evidence is limited to curation notes and referenced literature (PMIDs).
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PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. gnomAD MAF:0.00004.; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.899; PM3_Strong: Detected in trans with V245A and R261X, both pathogenic (PMID:7981714; PMID:16601866); PP4_Moderate: Detected in 3 patients (1 HPA, 1 PKU). BH4 deficiency excluded in 2 patients. (PMID:8533759; PMID:7981714; PMID:9012412; PMID:16601866). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PM3_Strong, PP4_Moderate).
Met criteria codes
Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.899
Absent from 1000G, ESP. gnomAD MAF:0.00004.
Detected in trans with V245A and R261X, both pathogenic
Patient F: V245A (VarID632, Path) /L194P. The mutations identified were confirmed by restriction analysis of PCR products reamplified from genomic DNA in affected subjects and their parents.
Patient 28 genotype: L194P/R261X (VarID610, Path). All the mutations identified were confirmed by analysing parental DNA, which also enabled us to follow the segregation of the mutations.
Detected in 3 patients (1 HPA, 1 PKU). BH4 deficiency excluded in 2 patients.
Likely same patient as Zschocke 1994. dihydrobiopterin reductase deficiency was excluded. HPA, 237 umol/L
L194P detected in 2 chromosomes of PKU patients from 4 centers in Great Britain.
Patient F had L194P. Phe levels 237 umol/L.
Patient 28 detected w/L194L (Mild PKU). A defect in the synthesis or recycling of tetrahydrobiopterin was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes.
Approved on: 2018-08-13
Published on: 2018-10-02
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