ClinVar Genomic variation as it relates to human health

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 71 of the ALPL protein (p.Arg71Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hypophosphatasia (PMID: 1409720, 31600233). 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 Arg54Cys. ClinVar contains an entry for this variant (Variation ID: 13663). 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%. Experimental studies have shown that this missense change affects ALPL function (PMID: 10839996). This variant disrupts the p.Arg71 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11438998, 22322541, 22397652, 25731960, 31760938). 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.211C>T (p.Arg71Cys) 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 247944 control chromosomes. c.211C>T has been reported in the literature in individuals affected with Autosomal Recessive Hypophosphatasia and autosomal dominant odonto type Hypophosphatasia (Henthorn_1992, Okawa_2019). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in diminished normal activity of ALPL in COS-1 cells (Fukushi-Irie_2000). A dominant-negative effect was also suggested in COS-7 cells (Fauvert_2009). Several different variant affecting the same codon has been classified as Pathogenic or Likely Pathogenic in ClinVar (c.211C>G p.Arg71Gly, c.211C>A p.Arg71Ser, c.212G>A p.Arg71His, c.212G>C p.Arg71Pro, c.1262C>T p.Ala421Val), supporting the critical relevance of codon 71 to ALPL protein function. The following publications have been ascertained in the context of this evaluation (PMID: 19500388, 10839996, 1409720, 31600233). ClinVar contains an entry for this variant (Variation ID: 13663). Based on the evidence outlined above, the variant was classified as pathogenic.

The ALPL c.211C>T variant is predicted to result in the amino acid substitution p.Arg71Cys. This variant in the heterozygous or along with a second variant in this gene has been reported in multiple individuals with hypophosphatasia (reported as Arg54Cys, Henthorn et al. 1992. PubMed ID: 1409720; Fauvert et al. 2009. PubMed ID: 19500388; Whyte et al. 2015. PubMed ID: 25731960; https://alplmutationdatabase.jku.at/table/). Different variants affecting the same amino acid (p.Arg71Ser, p.Arg71Gly, p.Arg71His, and p.Arg71Pro) have also been reported to be pathogenic (https://alplmutationdatabase.jku.at/table/; Human Gene Mutation Database; Whyte et al. 2015. PubMed ID: 25731960). Functional studies suggest that this variant leads to reduced alkaline phosphatase activity (Del Angel. 2020. PubMed ID: 32160374). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.