ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.591G>C (p.Leu197Phe)

dbSNP: rs281865442
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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 RCV000106361 SCV001146740 likely pathogenic Phenylketonuria 2019-05-04 reviewed by expert panel curation The c.591G>C (p.Leu197Phe) variant in PAH has been reported in 3 individuals with classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 18299955). This variant is absent in population databases (PM2). This variant was detected with a pathogenic variant (c.168+1G>A) and twice in the homozygous state (PM3). Multiple lines of computational evidence support a deleterious effect (SIFT, PolyPhen2, MutationTaster, REVEL=0.82). 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.
Baylor Genetics RCV000106361 SCV004209715 pathogenic Phenylketonuria 2023-01-01 criteria provided, single submitter clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre RCV000106361 SCV004805057 pathogenic Phenylketonuria 2024-03-17 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV000106361 SCV005836111 pathogenic Phenylketonuria 2024-08-29 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 197 of the PAH protein (p.Leu197Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 18299955, 32905092). ClinVar contains an entry for this variant (Variation ID: 120280). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Inserm U 954, Faculté de Médecine de Nancy RCV000106361 SCV000143861 probable-pathogenic Phenylketonuria no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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