ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.657G>T (p.Met219Ile)

gnomAD frequency: 0.00002  dbSNP: rs776117933
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001596919 SCV002242763 pathogenic not provided 2023-11-19 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 219 of the ALPL protein (p.Met219Ile). This variant is present in population databases (rs776117933, gnomAD 0.004%). This missense change has been observed in individuals with hypophosphatasia (Invitae). ClinVar contains an entry for this variant (Variation ID: 1224381). 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%. This variant disrupts the p.Met219 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24022022; Invitae). 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.
Baylor Genetics RCV003333168 SCV004041334 likely pathogenic Hypophosphatasia 2023-06-23 criteria provided, single submitter clinical testing
JKU Lab, Dept of Paediatrics, Johannes Kepler University RCV003333168 SCV004175719 likely pathogenic Hypophosphatasia 2023-12-05 criteria provided, single submitter clinical testing GnomAD low freq 0.0015908% (4). The functional test results and ACMG criteria applied can be looked up in the ALPL gene variant database. https://alplmutationdatabase.jku.at/
Baylor Genetics RCV003470872 SCV004195097 likely pathogenic Adult hypophosphatasia 2024-01-09 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001596919 SCV001832446 uncertain significance not provided 2019-11-30 flagged submission clinical testing

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