ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.106A>C (p.Thr36Pro)

gnomAD frequency: 0.00001  dbSNP: rs747167000
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
JKU Lab, Dept of Paediatrics, Johannes Kepler University RCV001813915 SCV002061002 likely pathogenic Hypophosphatasia 2021-12-16 criteria provided, single submitter clinical testing This variant is absent from large population studies. Functional studies performed at the JKU Hoegler lab showed reduced ALPL activity. ACMG Criteria used for classification: PS3_Mod, PM2_Sup, PM3_Sup, PP2_Sup, PP3_Sup, PP4_Sup.
PreventionGenetics, part of Exact Sciences RCV004552033 SCV004112974 uncertain significance ALPL-related disorder 2022-12-05 criteria provided, single submitter clinical testing The ALPL c.106A>C variant is predicted to result in the amino acid substitution p.Thr36Pro. This variant was reported in the homozygous state in a case of perinatal lethal hypophosphatasia (HPP) (Table S2, Del Angel et al. 2020. PubMed ID: 32160374; Supplementary table, Mornet et al. 2021. PubMed ID: 32973344). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, it is reported to result in reduced ALPL activity by a submitter; however, these molecular and functional data are unavailable for review, nor have they been peer reviewed (https://www.ncbi.nlm.nih.gov/clinvar/variation/1334401/). 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV003728016 SCV004523687 likely pathogenic not provided 2023-03-07 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 36 of the ALPL protein (p.Thr36Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypophosphatasia (PMID: 32160374, 32973344). ClinVar contains an entry for this variant (Variation ID: 1334401). 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.

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