Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001319736 | SCV001510495 | pathogenic | not provided | 2023-09-21 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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 ALPL protein function. ClinVar contains an entry for this variant (Variation ID: 1020192). This missense change has been observed in individual(s) with autosomal dominant hypophosphatasia and/or clinical features of ALPL-related conditions (PMID: 32160374; Invitae). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 410 of the ALPL protein (p.Phe410Leu). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002222697 | SCV002500458 | uncertain significance | not specified | 2022-03-02 | criteria provided, single submitter | clinical testing | Variant summary: ALPL c.1228T>C (p.Phe410Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251448 control chromosomes. c.1228T>C has been reported in the literature as a compound heterozygous genotype in at-least two individuals respectively affected with infantile and perinatal lethal Hypophosphatasia (example, del Angel_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |