Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001389815 | SCV001591298 | pathogenic | not provided | 2024-12-26 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 68 of the ALPL protein (p.Thr68Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 11760847, 25731960, 26432670, 31760938). 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: 1076060). 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) indicates that this missense variant is expected to disrupt ALPL protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV001389815 | SCV002588164 | pathogenic | not provided | 2022-04-29 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect with low protein levels at the cell surface and low enzymatic activity compares to wild type protein, supporting loss of function for homozygous state and dominant-negative effect for heterozygous state (Huang et al., 2020; Del Angel et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34662886, 11760847, 29236161, 25731960, 32160374, 26432670, 33093890, 31760938) |
| Fulgent Genetics, |
RCV002493933 | SCV002780066 | likely pathogenic | Adult hypophosphatasia; Childhood hypophosphatasia; Infantile hypophosphatasia | 2022-04-08 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV003469764 | SCV004193194 | pathogenic | Adult hypophosphatasia | 2023-12-26 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003479323 | SCV004222880 | pathogenic | Hypophosphatasia | 2023-11-19 | criteria provided, single submitter | clinical testing | Variant summary: ALPL c.203C>T (p.Thr68Met) results in a non-conservative amino acid change in the homodimer interface domain (Del Angel_2020) encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246608 control chromosomes. c.203C>T has been widely reported in the literature as biallelic compound heterozygous and heterozygous genotypes in individuals affected with variable presentations ranging from infantile/lethal to adult onset Hypophosphatasia (example, summarized in Del Angel_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Del Angel_2020). The most pronounced variant effect results in a very reduced ALPL enzyme activity relative to wild-type and a dominant negative effect in vitro. The following publication have been ascertained in the context of this evaluation (PMID: 32160374). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |