Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001245174 | SCV001418444 | pathogenic | not provided | 2025-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 495 of the ALPL protein (p.Gly495Ser). This variant is present in population databases (rs761079751, gnomAD 0.01%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 31707452; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 969756). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALPL protein function. Experimental studies have shown that this missense change affects ALPL function (PMID: 32160374). For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002282498 | SCV002571784 | uncertain significance | not specified | 2022-08-05 | criteria provided, single submitter | clinical testing | Variant summary: ALPL c.1483G>A (p.Gly495Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 240260 control chromosomes (gnomAD). c.1483G>A has been reported in the literature in at-least one homozygous individual affected with infantile Hypophosphatasia (Akiyama_2018, Michigami _2020). Furthermore, one ClinVar submitter reports observing the variant in additional individual(s) with hypophosphatasia, but did not provide evidence (i.e. genotype/phenotype information) for independent evaluation (SCV001418444.2). These data indicate that the variant may be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant had a residual enzyme activity of 0.73 relative to wild type and did not display dominant negative effect (Del Angel_2020). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic, and as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| JKU Lab, |
RCV001835229 | SCV005044394 | uncertain significance | Hypophosphatasia | 2024-04-09 | criteria provided, single submitter | clinical testing | The variant is present in GnomAD, with a reported frequency of 0.000895% (f = 0.00000895). The ACMG criteria applied can be looked up in the ALPL gene variant database. https://alplmutationdatabase.jku.at |
| Natera, |
RCV001835229 | SCV002094094 | uncertain significance | Hypophosphatasia | 2021-01-25 | no assertion criteria provided | clinical testing |