Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001238820 | SCV001411649 | pathogenic | not provided | 2023-11-24 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 136 of the ALPL protein (p.Arg136Cys). This variant is present in population databases (rs747762186, gnomAD 0.003%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 29724887, 30979366; 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: 964572). 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%. This variant disrupts the p.Arg136 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10094560, 11855933, 19500388). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| MGZ Medical Genetics Center | RCV002290655 | SCV002580908 | likely pathogenic | Childhood hypophosphatasia | 2022-06-13 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003235509 | SCV003934531 | pathogenic | Hypophosphatasia | 2023-05-15 | criteria provided, single submitter | clinical testing | Variant summary: ALPL c.406C>T (p.Arg136Cys) results in a non-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 allele was found at a frequency of 1.2e-05 in 250900 control chromosomes (gnomAD). c.406C>T has been reported in the literature in compound heterozygous (examples: Yu_2019, DelAngel_2020, and Zhang_2021) and heterozygous individuals affected with Hypophosphatasia (example: Taillandier_2017) and have shown both autosomal recessive and dominant inheritance. 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. The most pronounced variant effect results in <10% of normal activity (example: DelAngel_2020). Other variants affecting the same residue is associated with Hypophosphatasia (Taillandier_2017). The following publications have been ascertained in the context of this evaluation (PMID: 32160374, 29236161, 30979366, 34712267). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=3) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV001253680 | SCV004190647 | pathogenic | Adult hypophosphatasia | 2023-05-29 | criteria provided, single submitter | clinical testing | |
| Center for Molecular Medicine, |
RCV001257429 | SCV001433986 | likely pathogenic | Infantile hypophosphatasia | 2020-07-07 | no assertion criteria provided | clinical testing |