Submissions for variant NM_000478.6(ALPL):c.1426G>A (p.Glu476Lys)

gnomAD frequency: 0.00001  dbSNP: rs1057517173

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001047689	SCV001211667	pathogenic	not provided	2024-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 476 of the ALPL protein (p.Glu476Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant and autosomal recessive hypophosphatasia (PMID: 10094560, 22781519, 25731960, 28749478). This variant is also known as Glu459Lys, Glu399Lys. ClinVar contains an entry for this variant (Variation ID: 844755). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ALPL protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002479289	SCV002796145	likely pathogenic	Adult hypophosphatasia; Childhood hypophosphatasia; Infantile hypophosphatasia	2022-02-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004553586	SCV004114852	pathogenic	ALPL-related disorder	2022-11-01	criteria provided, single submitter	clinical testing	The ALPL c.1426G>A variant is predicted to result in the amino acid substitution p.Glu476Lys. This variant was found in the heterozygous condition in patients with childhood hypophosphatasia (Silva et al. 2012. PubMed ID: 22781519; Del Angel et al. 2020. PubMed ID: 32160374; http://www.sesep.uvsq.fr/03_hypo_mutations.php). This variant along with a second ALPL variant was reported in patients with perinatal, infantile HPP (Taillandier. 1999. PubMed ID: 10094560; Del Angel et al. 2020. PubMed ID: 32160374). Also, nearby variants affecting the same amino acid (c.1427A>G, p. Glu476Gly and c.1427A>C, p.Glu476Ala) were reported to be pathogenic for hypophosphatasia (http://www.sesep.uvsq.fr/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Baylor Genetics	RCV003462538	SCV004193786	pathogenic	Adult hypophosphatasia	2023-11-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004986759	SCV005607860	pathogenic	Inborn genetic diseases	2024-07-16	criteria provided, single submitter	clinical testing	The c.1426G>A (p.E476K) alteration is located in exon 12 (coding exon 11) of the ALPL gene. This alteration results from a G to A substitution at nucleotide position 1426, causing the glutamic acid (E) at amino acid position 476 to be replaced by a lysine (K). for loss of function ALPL-related hypophosphatasia; however, its clinical significance for dominant negative ALPL-related hypophosphatasia is uncertain This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in multiple individuals with a previous childhood diagnosis of hypophosphatasia, low ALPL serum levels, dento-oseous complications, and/or fractures (Silva, 2012; Whyte, 2015; Taillandier, 2018). Additionally, this variant has been identified in the homozygous state and/or in conjunction with other ALPL variants in individuals with lethal skeletal dysplasia or lethal perinatal hypophosphatasia; in at least one instance, the variants were identified in trans (Taillandier, 1999; Shamseldin, 2018; Huggins, 2020; Mornet, 2021). This amino acid position is highly conserved in available vertebrate species. In an in vitro functional study, this variant resulted in decreased activity compared to wild type (Del Angel, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001844265	SCV001870435	pathogenic	Infantile hypophosphatasia	2021-04-29	no assertion criteria provided	research