Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001300266 | SCV001489403 | pathogenic | not provided | 2024-08-08 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 341 of the ALPL protein (p.His341Arg). This variant is present in population databases (no rsID available, gnomAD 0.03%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 24276437). 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: 1003680). 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: 32160374). For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001830171 | SCV003929001 | likely pathogenic | Hypophosphatasia | 2023-04-21 | criteria provided, single submitter | clinical testing | Variant summary: ALPL c.1022A>G (p.His341Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.6e-06 in 150966 control chromosomes (gnomAD v3.1.2). c.1022A>G has been reported in the literature in individuals affected with Hypophosphatasia with evidence supporting an autosomal dominant mode of inheritance: one lethal perinatal case in a compound heterozygote (Taketani_2014) and one heterozygous family with moderate hypophosphatasia in an affected mother and fetus with abnormal bone structure (Sperelakis-Beedham_2021). These data indicate that the variant may be associated with disease. In vitro assays measuring TNSALP [tissue nonspecific alkaline phosphatase] enzymatic activity found that the variant had 4% residual activity when expressed alone in MDCK II cells, and 38% residual activity when co-expressed with WT ALPL, qualifying the variant as a Dominant-negative effect allele (Del Angel_2020). Two ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Fulgent Genetics, |
RCV005012740 | SCV005643577 | likely pathogenic | Adult hypophosphatasia; Childhood hypophosphatasia; Infantile hypophosphatasia | 2024-05-02 | criteria provided, single submitter | clinical testing | |
| Natera, |
RCV001830171 | SCV002094086 | uncertain significance | Hypophosphatasia | 2020-08-25 | no assertion criteria provided | clinical testing |