Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001903527 | SCV002169187 | pathogenic | not provided | 2024-11-05 | 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 452 of the ALPL protein (p.Glu452Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypophosphatasia (PMID: 12815606, 19500388, 25731960, 29236161; internal data). ClinVar contains an entry for this variant (Variation ID: 1405036). 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%. Experimental studies have shown that this missense change affects ALPL function (PMID: 19500388). For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002300620 | SCV002598633 | likely pathogenic | Hypophosphatasia | 2022-09-15 | criteria provided, single submitter | clinical testing | Variant summary: ALPL c.1354G>A (p.Glu452Lys) 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 was absent in 246068 control chromosomes. c.1354G>A has been reported in the literature as a compound heterozygous genotype in at-least three in individuals affected with Hypophosphatasia and also as a seemingly dominant variant segregating in one family with Hypophosphatasia (example, Del Angel_2020, Spentchian_2003, Seefried_2021, Moulin_2009, Mornet_2021). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Del Angel_2020). The most pronounced variant effect results in <10% of normal tissue nonspecific alkaline phosphatase (TNSALP) activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Baylor Genetics | RCV004571581 | SCV005053326 | likely pathogenic | Adult hypophosphatasia | 2023-11-27 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV005016799 | SCV005646788 | likely pathogenic | Adult hypophosphatasia; Childhood hypophosphatasia; Infantile hypophosphatasia | 2024-05-23 | criteria provided, single submitter | clinical testing |