ClinVar Genomic variation as it relates to human health

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP2,PP5.

ACMG classification criteria: PS3 supporting, PS4 moderate, PM2 moderate, PM3 strong, PP3 supporting

Variant summary: ALPL c.542C>T (p.Ser181Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251130 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ALPL causing Hypophosphatasia (4e-05 vs 0.0035), allowing no conclusion about variant significance. c.542C>T has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with infantile/perinatal-lethal/childhood/odontoid presentations of Hypophosphatasia (example, Seefried_2017, Del Angel_2020). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a partial reduction of normal activity (Del Angel_2020, Lia-Baldini_2001). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Observed as heterozygous with and without another ALPL variant in patients with hypophosphatasia in published literature (Spentchian et al., 2006; Nielson et al., 2012; Tenorio et al., 2017; Del Angel et al., 2020; Jandl et al., 2021); Published functional studies demonstrate a damaging effect on enzyme activity (Lia-Baldini et al., 2001); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21956185, 11479741, 28127875, 26783040, 17253930, 16583935, 32160374, 33191482, 33549410, 33601892, 31589614, 33977024, 37600704, 36444396)

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 181 of the ALPL protein (p.Ser181Leu). This variant is present in population databases (rs199590449, gnomAD 0.04%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 11479741, 16583935, 17253930, 32160374). 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 S164L. ClinVar contains an entry for this variant (Variation ID: 188798). 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: 11479741). For these reasons, this variant has been classified as Pathogenic.

The c.542C>T (p.S181L) alteration is located in exon 6 (coding exon 5) of the ALPL gene. This alteration results from a C to T substitution at nucleotide position 542, causing the serine (S) at amino acid position 181 to be replaced by a leucine (L)._x000D_ _x000D_ Based on the available evidence, this alteration is classified as likely pathogenic for autosomal recessive hypophosphatasia; however, it is unlikely to be causative of autosomal dominant hypophosphatasia. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (10/251130) total alleles studied. The highest observed frequency was 0.04% (4/10066) of Ashkenazi Jewish alleles. This alteration was detected in trans with a pathogenic ALPL mutation in a fetus with severe prenatal hypophosphatasia (Sperelakis-Beedham, 2021), as well as in the homozygous state in an individual with hypophosphatasia that presented in the neonatal period (Strandbech, 2021). In addition, this alteration was detected along with a second ALPL variant in an individual with subnormal serum alkaline phosphatase and disproportional dwarfism (Spentchian, 2006; Lia-Baldini, 2001), as well as in several other individuals with hypophosphatasia (del Angel, 2020). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.