ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.655A>G (p.Met219Val)

gnomAD frequency: 0.00002  dbSNP: rs772432010
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001351724 SCV001546218 pathogenic not provided 2024-01-04 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 219 of the ALPL protein (p.Met219Val). This variant is present in population databases (rs772432010, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of hypophosphatasia (PMID: 24022022; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1047062). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on ALPL function (PMID: 24022022). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV003469587 SCV004194319 likely pathogenic Adult hypophosphatasia 2023-11-18 criteria provided, single submitter clinical testing
Natera, Inc. RCV001825976 SCV002094065 uncertain significance Hypophosphatasia 2021-10-14 no assertion criteria provided clinical testing

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