Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Institute of Human Genetics, |
RCV001253054 | SCV001428575 | likely pathogenic | Adult hypophosphatasia | 2022-11-17 | criteria provided, single submitter | clinical testing | _x000D_ Criteria applied: PS4_MOD, PS3_SUP, PM2_SUP, PM5_SUP, PP3 |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001264416 | SCV001442547 | pathogenic | Hypophosphatasia | 2020-10-15 | criteria provided, single submitter | clinical testing | Variant summary: ALPL c.119C>T (p.Ala40Val) results in a non-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 1.2e-05 in 251466 control chromosomes. c.119C>T has been reported in the literature in multiple individuals affected with Hypophosphatasia (e.g. Mornet_1998, Taillandier_2000, Taillandier_2001, Whyte_2012, Taketani_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Zurutuza_1999). 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 uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. |
Invitae | RCV001389813 | SCV001591296 | pathogenic | not provided | 2024-01-26 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 40 of the ALPL protein (p.Ala40Val). This variant is present in population databases (rs770093969, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 11438998, 15660230, 22397652, 24276437). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Ala23Val. ClinVar contains an entry for this variant (Variation ID: 975919). 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: 10332035). For these reasons, this variant has been classified as Pathogenic. |
Baylor Genetics | RCV001253054 | SCV004194418 | likely pathogenic | Adult hypophosphatasia | 2023-09-19 | criteria provided, single submitter | clinical testing | |
Natera, |
RCV001264416 | SCV002094048 | pathogenic | Hypophosphatasia | 2021-09-28 | no assertion criteria provided | clinical testing |