Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000494553 | SCV000581990 | likely pathogenic | not provided | 2015-08-25 | criteria provided, single submitter | clinical testing | The P448L variant in the ALPL gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The P448L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P448L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (S445P, A446G, R450C, R450H, E452K) have been reported in the Human Gene Mutation Database in association with hypophosphatasia (Stenson et al., 2014), supporting the functional importance of this region of the protein. The P448L variant is a strong candidate for a disease-causing variant, however the possibility it may be a rare benign variant cannot be excluded |
| Labcorp Genetics |
RCV000494553 | SCV001382853 | uncertain significance | not provided | 2019-10-21 | criteria provided, single submitter | clinical testing | This sequence change replaces proline with leucine at codon 448 of the ALPL protein (p.Pro448Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ALPL-related conditions. ClinVar contains an entry for this variant (Variation ID: 429423). 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: "Probably Damaging"; Align-GVGD: "Not Available"). 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. |