ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.637C>T (p.Leu213Phe)

dbSNP: rs1131691945
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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 RCV000672958 SCV001146743 uncertain significance Phenylketonuria 2019-09-27 reviewed by expert panel curation The c.637C>T (p.Leu213Phe) variant in PAH is the same amino acid change as an established pathogenic variant, c.638T>C (p.Leu213Pro) VarID:92747. (PM5). This variant is absent in population databases (PM2). This variant has not been reported in the literature to our knowledge. Multiple lines of computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as uncertain significance for PAH.
GeneDx RCV000493939 SCV000583195 likely pathogenic not provided 2017-05-26 criteria provided, single submitter clinical testing The L213F substitution occurs at a position that is conserved across species.In silico analysis predicts this variant is probably damaging to the protein structure/function. Amissense variant at the same residue (L213P) has been reported in the Human Gene MutationDatabase in association with PKU (Stenson et al., 2014), supporting the functional importance of thisregion of the protein. In summary, we interpret L213F to be likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000672958 SCV003034535 uncertain significance Phenylketonuria 2024-02-17 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 213 of the PAH protein (p.Leu213Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PAH-related conditions. ClinVar contains an entry for this variant (Variation ID: 430401). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. This variant disrupts the p.Leu213 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8632937, 9521426, 19292873, 22112818, 23430547). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000672958 SCV000798118 uncertain significance Phenylketonuria 2018-02-26 no assertion criteria provided clinical testing

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