Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001248534 | SCV001422028 | likely pathogenic | not provided | 2019-03-14 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine with threonine at codon 111 of the ALPL protein (p.Ala111Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with hypophosphatasia (PMID: 24022022, 19500388, 9452105). This variant is also known as p.Ala94Thr in the literature. This missense variant has been reported substantially affect the alkaline phosphatase activity of the ALPL protein (PMID: 24022022, 19500388). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Gene |
RCV001248534 | SCV004034313 | pathogenic | not provided | 2023-09-01 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging dominant negative effect (Fauvert et al., 2009; Yang et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34662886, 33101980, 9452105, 24022022, 29595812, 32160374, 18386808, 19500388) |
| Genetics and Molecular Pathology, |
RCV003447575 | SCV004175564 | pathogenic | Hypophosphatasia | 2021-02-23 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV001029819 | SCV004192471 | pathogenic | Adult hypophosphatasia | 2023-08-26 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003447575 | SCV004223697 | pathogenic | Hypophosphatasia | 2023-11-02 | criteria provided, single submitter | clinical testing | Variant summary: ALPL c.331G>A (p.Ala111Thr) 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 8e-06 in 250952 control chromosomes. c.331G>A has been reported in the literature as a homozygous and compound heterozygous genotype in individuals affected with autosomal recessive hypophosphatasia with reported perinatal lethal phenotype (e.g.delAngel_2020). The variant has also been reported in at least one heterozygous individual with autosomal dominant odontohypophosphatasia (e.g.delAngel_2020). 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 enzyme activity in vitro (e.g. delAngel_2020). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. The following publication has been ascertained in the context of this evaluation (PMID: 32160374). All submitters classified the variant as pathogenic (n=2) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Bioscientia Institut fuer Medizinische Diagnostik Gmb |
RCV001029819 | SCV001192602 | pathogenic | Adult hypophosphatasia | 2019-06-25 | no assertion criteria provided | clinical testing |