ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.738G>T (p.Arg246Ser)

dbSNP: rs1223142821
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001264483 SCV001442657 pathogenic Hypophosphatasia 2020-10-26 criteria provided, single submitter clinical testing Variant summary: ALPL c.738G>T (p.Arg246Ser) results in a non-conservative amino acid change located in the Alkaline-phosphatase-like, core domain superfamily (IPR017850) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251412 control chromosomes. c.738G>T has been reported in the literature in individuals affected with infantile, perinatal lethal and childhood forms of Hypophosphatasia (example, del Angel_2020, Taillandier_2000). 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 (del Angel_2020). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV003320818 SCV004024779 pathogenic not provided 2023-08-15 criteria provided, single submitter clinical testing
Invitae RCV003320818 SCV004291728 pathogenic not provided 2024-01-25 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 246 of the ALPL protein (p.Arg246Ser). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with hypophosphatasia (PMID: 10679946, 11855933, 32160374). This variant is also known as R229S. ClinVar contains an entry for this variant (Variation ID: 984475). 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: 10679946, 32160374). For these reasons, this variant has been classified as Pathogenic.
Natera, Inc. RCV001264483 SCV002094070 pathogenic Hypophosphatasia 2020-12-28 no assertion criteria provided clinical testing

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