Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000758121 | SCV000886599 | likely pathogenic | Phenylketonuria | 2018-12-09 | reviewed by expert panel | curation | The c.827T>A (p.Met276Lys) variant in PAH is absent from population databases, and found in the same codon as a previously reported pathogenic variant (p.Met276Val). It has been identified in trans with a known pathogenic variant (I95del), in which a defect of BH4 metabolism was excluded as a cause of elevated phenylalanine (PMID: 25894915). |
Labcorp Genetics |
RCV000758121 | SCV001413944 | pathogenic | Phenylketonuria | 2019-10-15 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met276 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16198137, 16290003). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "not available"; PolyPhen-2: "Benign"; Align-GVGD: "Class not available"). This variant has been observed in several individuals affected with phenylketonuria (PMID: 16256386, 25894915, 29176022, 30459323, 30612563). ClinVar contains an entry for this variant (Variation ID: 102857). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with lysine at codon 276 of the PAH protein (p.Met276Lys). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and lysine. |
De |
RCV000089118 | SCV000119725 | not provided | not provided | no assertion provided | not provided |