ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.98C>T (p.Ala33Val)

gnomAD frequency: 0.00001  dbSNP: rs121918005
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001042961 SCV001206670 pathogenic not provided 2024-01-29 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 33 of the ALPL protein (p.Ala33Val). This variant is present in population databases (rs121918005, gnomAD 0.005%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 1409720, 15694177, 17253930, 22397652, 25731960). ClinVar contains an entry for this variant (Variation ID: 13667). 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 have shown that this missense change affects ALPL function (PMID: 15694177). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000014655 SCV003841204 pathogenic Infantile hypophosphatasia criteria provided, single submitter clinical testing
Baylor Genetics RCV003473099 SCV004194986 pathogenic Adult hypophosphatasia 2023-07-14 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV003473099 SCV004848783 likely pathogenic Adult hypophosphatasia 2022-11-03 criteria provided, single submitter clinical testing The p.Ala33Val variant in ALPL (also referred to in the literature as Ala16Val) has been reported in 6 individuals with hypophosphatasia (Henthorn 1992 PMID: 1409720, Brun-Heath 2005 PMID: 15694177, Whyte 2015 PMID: 25731960, Reis 2021 PMID: 34033304, Zhang 2021 PMID: 34712267). It has also been identified in 0.02% (1/5184) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID 13667). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant results in reduced protein activity compared to wild type (Brun-Heath 2005 PMID: 15694177, Del Angel 2020 PMID: 32160374); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hypophosphatasia. ACMG/AMP Criteria applied: PM3_Strong, PS3_Moderate, PP3, PM2_Supporting.
OMIM RCV000014655 SCV000034910 pathogenic Infantile hypophosphatasia 1992-10-15 no assertion criteria provided literature only
Natera, Inc. RCV001273156 SCV001455761 pathogenic Hypophosphatasia 2020-09-16 no assertion criteria provided clinical testing
Baylor Genetics RCV001333468 SCV001526050 uncertain significance Childhood hypophosphatasia 2018-08-08 flagged submission clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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