Submissions for variant NM_000478.6(ALPL):c.1444C>A (p.His482Asn)

gnomAD frequency: 0.00001  dbSNP: rs780857373

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001949280	SCV002247269	pathogenic	not provided	2023-03-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 1457579). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 25731960, 28663156). This variant is present in population databases (rs780857373, gnomAD 0.009%). This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 482 of the ALPL protein (p.His482Asn).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155449	SCV003844415	uncertain significance	not specified	2023-02-07	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.1444C>A (p.His482Asn) 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 allele was found at a frequency of 1.2e-05 in 243954 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1444C>A has been reported in the literature in individuals affected with Hypophosphatasia, including at least one case where the variant was reported in a patient with a known pathogenic variant (Nielson_2011, Whyte_2015, Saglam_2017). These data indicate that the variant may be associated with disease. Tissue-nonspecific alkaline phosphatase activity measured in transiently transfected cells showed residual activity >90% for the variant of interest (Del Angel_2020). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. In addition, a different variant located at the same codon has been reported in HGMD in association with Hypophosphatasia (p.H482Q) Based on the evidence outlined above, the variant was classified as uncertain significance.
JKU Lab, Dept of Paediatrics, Johannes Kepler University	RCV003448440	SCV004175701	likely pathogenic	Hypophosphatasia	2023-10-24	criteria provided, single submitter	clinical testing	GnomAD ƒ = 0.00001574 (European, non-Finnish). The functional test results and ACMG criteria applied can be looked up in the ALPL gene variant database. https://alplmutationdatabase.jku.at/
Baylor Genetics	RCV003471181	SCV004191306	likely pathogenic	Adult hypophosphatasia	2023-10-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004552136	SCV004740671	likely pathogenic	ALPL-related disorder	2023-10-24	criteria provided, single submitter	clinical testing	The ALPL c.1444C>A variant is predicted to result in the amino acid substitution p.His482Asn. This variant has been reported along with another ALPL variant in individuals with hypophosphatasia (Table 7, Whyte et al. 2015. PubMed ID: 25731960; Table 1: Case J, Sağlam et al. 2017. PubMed ID: 28663156). In vitro functional studies demonstrate this variant is able to retain >90% of enzyme activity compared to wildtype (Table S1, Del Angel et al. 2020. PubMed ID: 32160374). A different variant affecting the same amino acid (p.His482Gln) was reported in one child with hypophosphatasia (Su. 2021. PubMed ID: 34164522). At PrevetionGenetics, we have observed this variant in the compound heterozygous state in a newborn baby with clinical features of hypophosphatasia. This variant is reported in 0.0097% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-21904010-C-A). In summary, we this variant is interpreted as likely pathogenic.