ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.1460C>T (p.Ala487Val)

dbSNP: rs1229517379
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672960 SCV000798121 uncertain significance Infantile hypophosphatasia 2018-02-28 criteria provided, single submitter clinical testing
Center of Excellence in Genomics and Precision Dentistry, Faculty of Dentistry, Chulalongkorn University RCV001789781 SCV002032065 pathogenic Childhood hypophosphatasia criteria provided, single submitter clinical testing The compound heterozygous variants, c.1460C>T (p.Ala487Val) and c.1479C>A (p.Asn493Lys), in ALPL gene were identified in a patient diagnosed with hypochondroplasia (HCH) and hypophosphatasia (HPP). Her mother was heterozygous for the c.1460C>T (p.Ala487Val) while her father was heterozygous for the c.1479C>A (p.Asn493Lys). Both altered amino acid positions are highly conserved among species. She was also identified the with the heterozygous missense variant, c.1612A>G (p.Ile538Val) in FGFR3 (Porntaveetus et al., 2017).
Labcorp Genetics (formerly Invitae), Labcorp RCV001855588 SCV002236326 pathogenic not provided 2024-01-08 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 487 of the ALPL protein (p.Ala487Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive hypophosphatasia (PMID: 26432670, 28763161, 31077853). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 556895). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV003465521 SCV004193261 pathogenic Adult hypophosphatasia 2024-03-29 criteria provided, single submitter clinical testing

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