ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.1375G>A (p.Val459Met)

gnomAD frequency: 0.00001  dbSNP: rs1054159992
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669598 SCV000794368 uncertain significance Infantile hypophosphatasia 2017-10-07 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001378584 SCV001576186 pathogenic not provided 2023-12-17 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 459 of the ALPL protein (p.Val459Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ALPL-related conditions (PMID: 11438998, 27699270, 31707452). ClinVar contains an entry for this variant (Variation ID: 554044). 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: 31707452). This variant disrupts the p.Val459 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been observed in individuals with ALPL-related conditions (PMID: 19500388, 29724887), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004586861 SCV005077062 pathogenic Hypophosphatasia 2024-04-22 criteria provided, single submitter clinical testing Variant summary: ALPL c.1375G>A (p.Val459Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 244600 control chromosomes. c.1375G>A has been reported in the literature in individuals affected with Hypophosphatasia, either at a compound heterozygous state along with a second pathogenic variant, or at a single heterozygous state (example, DelAngel_2020, Michigami_2020, Sankaran_2020, Taillandier_2001). These data indicate that the variant is 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 in COS7 cells (Michigami_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32160374, 31707452, 32309015, 11438998). ClinVar contains an entry for this variant (Variation ID: 554044). Based on the evidence outlined above, the variant was classified as pathogenic.

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