ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.119C>T (p.Ala40Val)

gnomAD frequency: 0.00001  dbSNP: rs770093969
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, University of Leipzig Medical Center RCV001253054 SCV001428575 likely pathogenic Adult hypophosphatasia 2022-11-17 criteria provided, single submitter clinical testing _x000D_ Criteria applied: PS4_MOD, PS3_SUP, PM2_SUP, PM5_SUP, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001264416 SCV001442547 pathogenic Hypophosphatasia 2020-10-15 criteria provided, single submitter clinical testing Variant summary: ALPL c.119C>T (p.Ala40Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251466 control chromosomes. c.119C>T has been reported in the literature in multiple individuals affected with Hypophosphatasia (e.g. Mornet_1998, Taillandier_2000, Taillandier_2001, Whyte_2012, Taketani_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Zurutuza_1999). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001389813 SCV001591296 pathogenic not provided 2024-01-26 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 40 of the ALPL protein (p.Ala40Val). This variant is present in population databases (rs770093969, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 11438998, 15660230, 22397652, 24276437). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Ala23Val. ClinVar contains an entry for this variant (Variation ID: 975919). 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: 10332035). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001253054 SCV004194418 likely pathogenic Adult hypophosphatasia 2023-09-19 criteria provided, single submitter clinical testing
Natera, Inc. RCV001264416 SCV002094048 pathogenic Hypophosphatasia 2021-09-28 no assertion criteria provided clinical testing

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