ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.859C>G (p.Leu287Val)

gnomAD frequency: 0.00001  dbSNP: rs781096854
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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 RCV000758129 SCV000886611 likely pathogenic Phenylketonuria 2018-12-09 reviewed by expert panel curation The c.859C>G (p.Leu287Val) variant in PAH is found with low allele frequency in population databases (3.0e-5). It has been identified in trans with pathogenic variants in two individuals in the literature (P281L and A300S, PMID: 12409276), and in one of those patients a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine (PMID: 16198137). . In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3.
Labcorp Genetics (formerly Invitae), Labcorp RCV000758129 SCV005836110 pathogenic Phenylketonuria 2024-01-27 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 287 of the PAH protein (p.Leu287Val). This variant is present in population databases (rs781096854, gnomAD 0.002%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 12409276, 16198137, 26210745). ClinVar contains an entry for this variant (Variation ID: 619164). 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%. For these reasons, this variant has been classified as Pathogenic.

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