Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001389868 | SCV001591390 | pathogenic | not provided | 2021-06-27 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Tyr101*) in the ALPL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALPL are known to be pathogenic (PMID: 3174660, 10679946, 19500388). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with ALPL-related conditions. This variant is present in population databases (rs746273959, ExAC 0.003%). |
| Laboratory for Molecular Medicine, |
RCV001449738 | SCV001653009 | likely pathogenic | Infantile hypophosphatasia | 2020-06-11 | criteria provided, single submitter | clinical testing | The p.Tyr101X variant in ALPL has been reported in the heterozygous state in 1 individual with osteoporosis and low circulating concentrations of alkaline phosphatase (AP; Alonso 2019 PMID: 31793067). It has also been identified in 0.004% (4/113178) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 101, which is predicted to lead to a truncated or absent protein. While hypophosphatasia can be inherited in an autosomal dominant or autosomal recessive manner, loss-of-function variants like the p.Tyr101X variant are primarily associated with recessive inheritance. Although individuals harboring heterozygous loss-of-function variants may have low serum AP levels, they are typically asymptomatic. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hypophosphatasia. ACMG/AMP Criteria applied: PVS1, PM2. |
| Baylor Genetics | RCV003469765 | SCV004193039 | pathogenic | Adult hypophosphatasia | 2023-05-03 | criteria provided, single submitter | clinical testing |