Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000436688 | SCV000517209 | pathogenic | not provided | 2015-05-13 | criteria provided, single submitter | clinical testing | The Q301K substitution has not been published as a pathogenic variant, nor has it beenreported as a benign polymorphism to our knowledge. Q301K was not observed in approximately 6500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. TheQ301K substitution occurs at a position that is conserved across species, in silico analysis predicts thisvariant is probably damaging to the protein structure/function, and missense variants at the same position(Q301P, Q301H) and in nearby residues (P292L/M, L293S, D296G, R297C/L/H, F299C, A300S/V,S303A/P, Q304R, I306V, G307D, L308F/V, A309D/V, S310Y/F, L311P) have been reported in theHuman Gene Mutation Database in association with phenylketonuria/ hyperphenylalaninemia (Stenson etal., 2014), supporting the functional importance of this region of the protein. Therefore, we interpretQ301K to be a pathogenic variant. |
| Labcorp Genetics |
RCV005090722 | SCV005799964 | uncertain significance | Phenylketonuria | 2024-03-28 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 301 of the PAH protein (p.Gln301Lys). 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: 379788). 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.Gln301 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 19292873, 21307867, 32668217; BIOPKU http://www.biopku.org), which suggests that this may be a clinically significant amino acid residue. 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. |
| Department of Pathology and Laboratory Medicine, |
RCV005090722 | SCV006057714 | likely pathogenic | Phenylketonuria | 2022-11-01 | criteria provided, single submitter | research |