ClinVar Genomic variation as it relates to human health

Variant summary: The ALPL c.815G>A (p.Arg272His) variant (alternatively also known as R255H) involves the alteration of a conserved nucleotide, resulting in a missense change residing in the alkaline-phosphatase-like core domain (InterPro). 3/3 in silico tools predict damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.0000083 (1/120878 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic ALPL variant (0.0035355). The variant has been identified in a homozgous patient with hypophosphatasia (HPP), with in vitro functional studies showing that residual enzyme activity is < 10% of WT levels (Brun-Heath_MGM_2005). In addition, molecular modeling suggests the variant lies within a conserved calcium-binding domain, which is supported by the fact that several variants at the same codon are found in HPP patients (R272C, R272L), suggesting the residue is critical for protein function. The variant has not been classified in reputable databases or by clinical diagnostics laboratories. Taken together, this variant is classified as likely pathogenic until additional HPP patients with the variant are identified.

Published functional studies demonstrate a damaging effect (Brun-Heath et al., 2005); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32160374, 29236161, 28663156, 19500388, 15694177)

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg272 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17253930, 18559907, 24276437, 24378058). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 272 of the ALPL protein (p.Arg272His). This variant is present in population databases (rs781272386, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of autosomal dominant and recessive ALPL-related conditions (PMID: 15694177, 28663156, 29236161). This variant is also known as R255H. ClinVar contains an entry for this variant (Variation ID: 495882). 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. Experimental studies have shown that this missense change affects ALPL function (PMID: 15694177).

The ALPL c.815G>A; p.Arg272His variant (rs781272386), also known as R255H, is reported in the literature in individuals affected with autosomal dominant and recessive hypophosphatasia (Brun-Heath 2005, Saglam 2017, Taillandier 2018). This variant is also reported in ClinVar (Variation ID: 495882) and is found in the non-Finnish European population with an allele frequency of 0.003% (4/129072 alleles) in the Genome Aggregation Database. Additionally, other variants at this codon (c.814C>T, p.Arg272Cys; c.815G>T, p.Arg272Leu) have been reported in individuals with ALPL- related conditions and are considered pathogenic (Del Angel 2020, Zhang 2021). Functional analyses of the variant protein show reduced enzyme activity (Brun-Heath 2005, Del Angel 2020). Computational analyses predict that this variant is deleterious (REVEL: 0.896). Based on available information, this variant is considered to be pathogenic. References: Brun-Heath I et al. Characterization of 11 novel mutations in the tissue non-specific alkaline phosphatase gene responsible for hypophosphatasia and genotype-phenotype correlations. Mol Genet Metab. 2005 Mar;84(3):273-7. PMID: 15694177. Del Angel G et al. Large-scale in vitro functional testing and novel variant scoring via protein modeling provide insights into alkaline phosphatase activity in hypophosphatasia. Hum Mutat. 2020 Jul;41(7):1250-1262. PMID: 32160374. Saglam H et al. Clinical and Genetic Findings of Turkish Hypophosphatasia Cases. J Clin Res Pediatr Endocrinol. 2017 Sep 1;9(3):229-236. PMID: 28663156. Taillandier A et al. Genetic analysis of adults heterozygous for ALPL mutations. J Bone Miner Metab. 2018 Nov;36(6):723-733. PMID: 29236161. Zhang L et al. Molecular diagnosis for 55 fetuses with skeletal dysplasias by whole-exome sequencing: A retrospective cohort study. Clin Genet. 2021 Aug;100(2):219-226. PMID: 33942288.