ClinVar Genomic variation as it relates to human health

Absent in GnomAD. Further information about the ACMG criteria applied can be looked up in the ALPL gene variant database. https://alplmutationdatabase.jku.at/

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 220 of the ALPL protein (p.Gly220Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with infantile hypophosphatasia (PMID: 11438998). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as G203V. 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%. This variant disrupts the p.Gly220 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22397652, 25731960). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Variant summary: ALPL c.659G>T (p.Gly220Val) 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 251476 control chromosomes. c.659G>T has been reported in the literature in the compound heterozygous state in individuals affected with autosomal recessive Hypophosphatasia and in the heterozygous state in affected individuals without strong strong evidence for autosomal dominant inheritance (e.g. Taillandier_2001, Tenorio_2017, Del Angel_2020, Tornero_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a different variant affecting the same codon has been classified as pathogenic (c.659G>C, p.Gly220Ala), supporting the critical relevance of codon 220 to ALPL protein function. The following publications have been ascertained in the context of this evaluation (PMID: 32160374, 31267001, 11438998, 28127875, 35241128). ClinVar contains an entry for this variant (Variation ID: 2664952). Based on the evidence outlined above, the variant was classified as likely pathogenic.