Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000169122 | SCV000220331 | likely pathogenic | Infantile hypophosphatasia | 2014-05-20 | criteria provided, single submitter | literature only | |
| Labcorp Genetics |
RCV002515193 | SCV003522640 | pathogenic | not provided | 2023-06-23 | criteria provided, single submitter | clinical testing | 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. Experimental studies have shown that this missense change affects ALPL function (PMID: 32160374). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188792). This variant is also known as p.Glu274Lys. This missense change has been observed in individual(s) with hypophosphatasia (PMID: 9781036, 28127875, 32160374). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 291 of the ALPL protein (p.Glu291Lys). |
| ARUP Laboratories, |
RCV002515193 | SCV003799379 | likely pathogenic | not provided | 2022-03-11 | criteria provided, single submitter | clinical testing | The ALPL c.871G>A; p.Glu291Lys, variant (rs), also known as E274K, is reported in the literature in individuals affected with infantile HPP who also carried additional variants pathogenic variants of ALPL (Mornet 1998, Del Angel 2020 and Tao 2021). In vitro functional analyses of the p.Glu291Lys demonstrate minimal phosphatase activity consistent with other pathogenic variants of ALPL (Del Angel 2020). This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Based on available information, this variant is considered to be likely pathogenic. References: Mornet E et al. Identification of fifteen novel mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in European patients with severe hypophosphatasia. Eur J Hum Genet. Jul-Aug 1998;6(4):308-14. PMID: 9781036 Del Angel G et al. Large-scale in vitro functional testing and novel variant scoring via protein modeling provide insights into alkaline phosphatase activity in hypophosphatasia. Hum Mutat. 2020 Tao D et al. [Genetic analysis of two couples with a history of multiple fetal malformations]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2021 Jul 10;38(7):643-646. PMID: 34247368 [Article in Chinese] |