ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.341C>T (p.Ala114Val)

gnomAD frequency: 0.00003  dbSNP: rs762915678
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, University of Leipzig Medical Center RCV001253667 SCV001429505 uncertain significance Adult hypophosphatasia 2017-11-07 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV005057166 SCV005698012 likely pathogenic not provided 2024-10-17 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 114 of the ALPL protein (p.Ala114Val). This variant is present in population databases (rs762915678, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of hypophosphatasia (PMID: 29236161). ClinVar contains an entry for this variant (Variation ID: 976384). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 32160374). This variant disrupts the p.Ala114 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11547844; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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