ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.1310C>T (p.Ala437Val)

gnomAD frequency: 0.00001  dbSNP: rs1437787933
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001041986 SCV001205641 uncertain significance not provided 2024-02-19 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 437 of the ALPL protein (p.Ala437Val). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 36361766). ClinVar contains an entry for this variant (Variation ID: 840083). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
JKU Lab, Dept of Paediatrics, Johannes Kepler University RCV001827252 SCV005627759 uncertain significance Hypophosphatasia 2024-12-10 criteria provided, single submitter curation This missense variant is present in GnomAD 4.1 (f = 5.58e-6) and affects a highly conserved amino acid in the crown domain. The variant is predicted to affect protein function (REVEL score: 0.328). Splice-prediction algorithms predict no effect on splicing. This variant has been reported in the literature in individuals affected with ALPL-related conditions (PMID 38884565). The results of the functional testing and the applied ACMG criteria can be viewed at: https://alplmutationdatabase.jku.at/table/
Natera, Inc. RCV001827252 SCV002094090 uncertain significance Hypophosphatasia 2020-02-26 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004553575 SCV004750149 uncertain significance ALPL-related disorder 2024-02-16 no assertion criteria provided clinical testing The ALPL c.1310C>T variant is predicted to result in the amino acid substitution p.Ala437Val. This variant was reported in two individuals with hypophosphatasia (Glotov et al. 2022. PubMed ID: 36361766; Feurstein et al. et al. 2022. PubMed ID: 36514157). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At PreventionGenetics, this variant was observed in 3 individuals undergoing test for ALPL. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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