ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.1367G>A (p.Gly456Glu)

dbSNP: rs1644753808
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002014284 SCV002301937 likely pathogenic not provided 2022-07-19 criteria provided, single submitter clinical testing 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. 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. This variant disrupts the p.Gly456 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8954059, 19500388, 31641588). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ALPL function (PMID: 32160374). ClinVar contains an entry for this variant (Variation ID: 1511003). This variant has not been reported in the literature in individuals affected with ALPL-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine with glutamic acid at codon 456 of the ALPL protein (p.Gly456Glu). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and glutamic acid.
JKU Lab, Dept of Paediatrics, Johannes Kepler University RCV003448446 SCV004175191 likely pathogenic Hypophosphatasia 2023-10-24 criteria provided, single submitter clinical testing Absent in GnomAD. Functional testing at the JKU lab showed reduced ALP residual activity. The functional test results and ACMG criteria applied can be looked up in the ALPL gene variant database. https://alplmutationdatabase.jku.at/

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