Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
JKU Lab, |
RCV003448655 | SCV004175887 | likely pathogenic | Hypophosphatasia | 2023-12-05 | criteria provided, single submitter | clinical testing | GnomAD frequency 0.00079535% (2). Functional testing at the JKU lab showed reduced ALP residual activity. The functional test results and ACMG criteria applied can be looked up in the ALPL gene variant database. https://alplmutationdatabase.jku.at/ |
Baylor Genetics | RCV003459864 | SCV004191881 | likely pathogenic | Adult hypophosphatasia | 2023-10-19 | criteria provided, single submitter | clinical testing | |
Invitae | RCV003553944 | SCV004290750 | pathogenic | not provided | 2023-12-22 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 236 of the ALPL protein (p.Tyr236Cys). This variant is present in population databases (rs533959092, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive hypophosphatasia (PMID: 34712267). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |