ClinVar Genomic variation as it relates to human health

The ALPL c.1417G>A; p.Gly473Ser variant, also known as G456S, is reported in the literature in the compound heterozygous state in individuals affected with hypophosphatasia (Martins 2019, Mornet 1998). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 473 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Martins L et al. A novel combination of biallelic ALPL mutations associated with adult hypophosphatasia: A phenotype-genotype association and computational analysis study. Bone. 2019 Aug;125:128-139. Mornet E et al. Identification of fifteen novel mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in European patients with severe hypophosphatasia. Eur J Hum Genet. 1998 Jul-Aug;6(4):308-14.

Reported in childhood and adult cases of HPP in published literature; including at least one patient with a variant on the opposite allele (in trans) (Martins et al., 1998; Tenorio et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); 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: 35320273, 9781036, 31077853, 28127875)

Variant summary: ALPL c.1417G>A (p.Gly473Ser) 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 244634 control chromosomes (gnomAD). c.1417G>A has been reported in the literature in the compound heterozygous state in an individual affected with perinatal autosomal recessive Hypophosphatasia where it was confirmed to be in trans with a pathogenic variant (Mornet_1998) and in the compound heterozygous state in an individual with the adult-onset form of the disease (Martins_2019). The variant has also been reported in heterozygous individuals with clinical features of Hypophosphatasia, including low alkaline phosphatase levels, indicating that carriers of this variant can experience mild symptoms (e.g. Riancho-Zarrabeitia_2016, Tenorio_2017, Martins_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31077853, 9781036, 26783040, 28127875). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 473 of the ALPL protein (p.Gly473Ser). 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: 9781036, 28127875, 31077853). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 845286). 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.