Submissions for variant NM_000478.6(ALPL):c.1403C>T (p.Ala468Val)

gnomAD frequency: 0.00001  dbSNP: rs766656419

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001380649	SCV001578777	pathogenic	not provided	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 468 of the ALPL protein (p.Ala468Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hypophosphatasia (PMID: 31600233; Invitae). ClinVar contains an entry for this variant (Variation ID: 427766). 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: 32160374). This variant disrupts the p.Ala468 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12815606). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001805108	SCV002050752	likely pathogenic	Hypophosphatasia	2021-12-04	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.1403C>T (p.Ala468Val) 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 allele was found at a frequency of 8.2e-06 in 245090 control chromosomes. c.1403C>T has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with infantile onset Hypophosphatasia (example, Okawa_2019) and as a heterozygous genotype in one individual with adult onset Hypophosphatasia (HPP) (example, Talliandier_2018). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function (DelAngel_2020). The most pronounced variant effect results in <10% of normal TNSALP enzymatic activity reported as mutant activity relative to WT value of 0.039 (4%). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic citing an overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV002464210	SCV002759364	pathogenic	Adult hypophosphatasia	2022-12-07	criteria provided, single submitter	clinical testing
JKU Lab, Dept of Paediatrics, Johannes Kepler University	RCV001805108	SCV004175731	likely pathogenic	Hypophosphatasia	2023-12-05	criteria provided, single submitter	clinical testing	GenomAD ƒ = 0.000193 (East Asian). Further information about the ACMG criteria applied can be looked up in the ALPL gene variant database. https://alplmutationdatabase.jku.at/
Baylor Genetics	RCV002464210	SCV004191948	likely pathogenic	Adult hypophosphatasia	2023-10-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001380649	SCV004564272	likely pathogenic	not provided	2023-01-04	criteria provided, single submitter	clinical testing	The ALPL c.1403C>T; p.Ala468Val variant (rs766656419) is reported in the literature in an individual with infantile-onset hypophosphatasia (HPP) that carried a second missense variant (Okawa 2019) and a heterozygous individual with symptoms of adult-onset HPP (Taillandier 2018). This variant is found in the general population with an overall allele frequency of 0.001% (3/276456 alleles) in the Genome Aggregation Database. The alanine at codon 468 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.944). Consistent with these predictions, functional assays show significantly reduced enzymatic activity of the variant protein (Del Angel 2020). Additionally, another variant at this codon (c.1402G>A; p.Ala468Thr) has been reported in homozygous individuals with HPP and is considered disease-causing (Spentchian 2003, Del Angel 2020). Based on available information, the p.Ala468Val variant is considered to be likely pathogenic. References: 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. Okawa R et al. Japanese nationwide survey of hypophosphatasia reveals prominent differences in genetic and dental findings between odonto and non-odonto types. PLoS One. 2019 Oct 10;14(10):e0222931. PMID: 31600233. Spentchian M et al. Severe hypophosphatasia: characterization of fifteen novel mutations in the ALPL gene. Hum Mutat. 2003 Jul;22(1):105-6. PMID: 12815606. Taillandier A et al. Genetic analysis of adults heterozygous for ALPL mutations. J Bone Miner Metab. 2018 Nov;36(6):723-733. PMID: 29236161.
Institute of Human Genetics, University of Wuerzburg	RCV000490707	SCV000579354	uncertain significance	Low alkaline phosphatase		no assertion criteria provided	clinical testing