Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001939650 | SCV002232561 | pathogenic | not provided | 2023-08-17 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 1455037). 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. Experimental studies have shown that this missense change affects ALPL function (PMID: 23509830). For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with autosomal recessive hypophosphatasia (PMID: 20924064, 23509830, 30138938). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 374 of the ALPL protein (p.Val374Met). This variant is present in population databases (rs552831415, gnomAD 0.02%). |
| Fulgent Genetics, |
RCV002492124 | SCV002779231 | likely pathogenic | Adult hypophosphatasia; Childhood hypophosphatasia; Infantile hypophosphatasia | 2022-03-10 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003401965 | SCV004122527 | likely pathogenic | Hypophosphatasia | 2023-10-05 | criteria provided, single submitter | clinical testing | Variant summary: ALPL c.1120G>A (p.Val374Met) 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 1.6e-05 in 251494 control chromosomes (gnomAD). c.1120G>A has been reported in the literature in the compound heterozygous state in individuals, predominantly children, affected with and/or with features of Autosomal Recessive Hypophosphatasia, including at least one case were it was confirmed to be in trans with a pathogenic variant also associated with an autosomal recessive inheritance pattern (e.g. Liu_2010, Huang_2018, Del Angel_2020). The variant has also been reported in the heterozygous state in at least two adults with persistent hypophosphatasaemia (e.g. Alonso_2020, Tornero_2022). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (Zhu_2012, Del Angel_2020). The most pronounced variant effect results in approximately 60% of alkaline phosphatase activity and 75% mineralization ability compared to the wild type protein (Zhu_2012). The following publications have been ascertained in the context of this evaluation (PMID: 32160374, 30138938, 20924064, 35241128, 23509830, 31793067). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Baylor Genetics | RCV003471161 | SCV004193687 | likely pathogenic | Adult hypophosphatasia | 2023-10-24 | criteria provided, single submitter | clinical testing |