Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000671010 | SCV000795945 | uncertain significance | Infantile hypophosphatasia | 2017-11-30 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001861800 | SCV002258655 | pathogenic | not provided | 2023-03-12 | criteria provided, single submitter | clinical testing | 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: 555231). This missense change has been observed in individual(s) with clinical features of hypophosphatasia (PMID: 17253930; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 123 of the ALPL protein (p.Ala123Asp). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002265848 | SCV002548043 | uncertain significance | not specified | 2022-05-17 | criteria provided, single submitter | clinical testing | Variant summary: ALPL c.368C>A (p.Ala123Asp) 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 251066 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.368C>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with features of Perinatal onset Hypophosphatasia who continues to be subsequently cited by others (example, Spentchian_2006 cited in Del Angel_2020, Mornet_2021). These data do not allow any conclusion about variant significance. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported although the compound heterozygous genotype reported a low Serum ALP enzyme activity (Spentchian_2006). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as likely pathogenic citing structural predictions and one laboratory classified the variant as uncertain significance. Both submitters cite overlapping literature evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Baylor Genetics | RCV003465505 | SCV004193841 | likely pathogenic | Adult hypophosphatasia | 2024-03-21 | criteria provided, single submitter | clinical testing |