Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001210319 | SCV001381802 | pathogenic | not provided | 2024-05-12 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 359 of the ALPL protein (p.Ile359Met). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 22397652, 25100374; Invitae). 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: 940683). 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%. Experimental studies have shown that this missense change affects ALPL function (PMID: 30446691). For these reasons, this variant has been classified as Pathogenic. |
| Fulgent Genetics, |
RCV002497720 | SCV002813844 | pathogenic | Adult hypophosphatasia; Childhood hypophosphatasia; Infantile hypophosphatasia | 2024-06-03 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV003462706 | SCV004192595 | likely pathogenic | Adult hypophosphatasia | 2024-03-17 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV005236686 | SCV005883411 | pathogenic | Hypophosphatasia | 2024-12-16 | criteria provided, single submitter | clinical testing | Variant summary: ALPL c.1077C>G (p.Ile359Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251480 control chromosomes (gnomAD). c.1077C>G has been reported in the literature in individuals affected with Hypophosphatasia (Whyte_2012, Ukarapong_2014, Kramer_2020, Rush_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant disrupts protein function (Williams_2018). The following publications have been ascertained in the context of this evaluation (PMID: 33160095, 34633109, 25100374, 22397652, 30446691). ClinVar contains an entry for this variant (Variation ID: 940683). Based on the evidence outlined above, the variant was classified as pathogenic. |