ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.868C>T (p.His290Tyr)

dbSNP: rs1486763160
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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 RCV000993602 SCV001146693 likely pathogenic Phenylketonuria 2019-08-11 reviewed by expert panel curation The c.868C>T (p.His290Tyr) variant in PAH has been reported in 1 individual with PKU (BH4 deficiency excluded) detected in trans with p.R408E (Pathogenic in ClinVar; PP4_Moderate, PM3; PMID: 22526846). This variant is absent in population databases (PM2). Computational evidence suggests a damaging effect. 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000993602 SCV002301801 pathogenic Phenylketonuria 2024-03-26 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 290 of the PAH protein (p.His290Tyr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 22526846, 29499199; Invitae). ClinVar contains an entry for this variant (Variation ID: 805807). 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 expected to disrupt PAH protein function with a positive predictive value of 80%. This variant disrupts the p.His290 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 26210745, 26666653), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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