ClinVar Genomic variation as it relates to human health

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 327 of the ALPL protein (p.Phe327Leu). This variant is present in population databases (rs121918010, gnomAD 0.1%). This missense change has been observed in individuals with autosomal recessive hypophosphatasia (PMID: 8954059, 9814472, 12412800, 15660230). This variant is also known as p.Phe310Leu. ClinVar contains an entry for this variant (Variation ID: 13673). 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: 8954059, 9814472, 15137467, 17916236, 18455459). For these reasons, this variant has been classified as Pathogenic.

The variant is present in GnomAD with a reported frequency of 0.001738 (v4.1) in the East Asian population. The ACMG criteria applied can be looked up in the ALPL gene variant database. https://alplmutationdatabase.jku.at

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Multiple functional studies show the variant results in approximately 70% activity levels compared to wild type, while an additional study suggests the activity may be similar to wild type. The data suggest the variant may contribute to a less severe phenotype; however, this has not been fully established (Ozono K et al., 1996; Cai G et al., 1998; Takinami H et al., 2004; Del Angel G et al., 2020); This variant is associated with the following publications: (PMID: 31857675, 9814472, 8954059, 15137467, 9452105, 24276437, 31014398, 31707452, 31600233, 20301329, 31760938, 32160374, 33452237, 11810413)

Variant summary: The ALPL c.979T>C (p.Phe327Leu) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 7/120210 control chromosomes at a frequency of 0.0000582, which does not exceed the estimated maximal expected allele frequency of a pathogenic ALPL variant (0.0035355). This variant has been identified as one of the most frequent mutations in patients with mild type hypophosphatasia in Japan. Functional study showed that this variant resulted in decreased enzyme activity and mineralization in cultured cells. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

This variant is interpreted as a Likely Pathogenic, for Hypophosphatasia, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS3 => Well-established functional studies show a deleterious effect (PMID:18455459).

The ALPL c.979T>C (p.Phe327Leu) missense variant is also described in the literature as p.Phe310Leu. Across a selection of the available literature, the p.Phe327Leu variant has been identified in a compound heterozygous state in at least 12 individuals with hypophosphatasia (Ozono et al. 1996; Takinami et al. 2004; Taketani et al. 2014). The p.Phe327Leu variant was also identified in a heterozygous state in two parents of affected probands who were found to have low ALP levels, but mild to absent clinical features (Ozono et al. 1996; Takinami et al. 2004). The p.Phe327Leu variant was absent from at least 40 control individuals and is reported at a frequency of 0.00111 in the East Asian population of the Genome Aggregation Database. Expression of the p.Phe327Leu variant in COS-7 cells resulted in ALP activity that was approximately 65% of wild type (Ozono et al. 1996; Takinami et al. 2004). The p.Phe327Leu variant was also significantly more heat labile than wild type (Takinami et al. 2004). Based on the collective evidence, the p.Phe327Leu variant is classified as pathogenic for hypophosphatasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

NM_000478.4(ALPL):c.979T>C(F327L, aka F310L) is classified as likely pathogenic in the context of hypophosphatasia. Sources cited for classification include the following: PMID 24276437, 15137467, 15660230, 9452105 and 18455459. Classification of NM_000478.4(ALPL):c.979T>C(F327L, aka F310L) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

The ALPL c.979T>C variant is predicted to result in the amino acid substitution p.Phe327Leu. In the compound heterozygous state, this variant has been documented to be pathogenic for mild or severe types of hypophosphatasia (Taketani et al. 2014. PubMed ID: 24276437; Ozono et al. 1996. PubMed ID: 8954059, reported as p.Phe310Leu; Michigami et al. 2019. PubMed ID: 31707452; Mao et al. 2019. PubMed ID: 31760938). Alternate nucleotide changes affecting the same amino acid (p.Phe327Cys, p.Phe327Gly) have been reported to be pathogenic (Mornet et al. 2001. PubMed ID: 11395499, reported as p.Phe310Cys; Taillandier et al. 2001. PubMed ID: 11438998, reported as p.Phe310Gly). This variant is reported in 0.11% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.