Submissions for variant NM_000478.6(ALPL):c.332C>T (p.Ala111Val)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
JKU Lab, Dept of Paediatrics, Johannes Kepler University	RCV005052133	SCV005627574	likely pathogenic	Hypophosphatasia	2024-12-10	criteria provided, single submitter	curation	This missense variant is not present in GnomAD 4.1 and affects a highly conserved amino acid in the active site domain. The variant is predicted to affect protein function (REVEL score: 0.967). Splice-prediction algorithms predict no effect on splicing. In vitro functional studies showed reduced ALP activity with dominant negative effect. This variant has not been reported in the literature in individuals affected with ALPL-related conditions. The results of the functional testing and the applied ACMG criteria can be viewed at: https://alplmutationdatabase.jku.at/table/
Labcorp Genetics (formerly Invitae), Labcorp	RCV005105382	SCV005728534	likely pathogenic	not provided	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 111 of the ALPL protein (p.Ala111Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant hypophosphatasia (internal data). 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%. This variant disrupts the p.Ala111 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9452105, 19500388, 24022022; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.