Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000489304 | SCV000577069 | pathogenic | not provided | 2017-04-11 | criteria provided, single submitter | clinical testing | The S295X variant in the WNT1 gene has been reported previously in the homozygous state in individuals of Hmong background with osteogenesis imperfecta (Laine et al., 2013; Pyott et al., 2013). This variant is predicted to cause loss of normal protein function through protein truncation, as the last 76 amino acids of the protein are lost. Functional studies demonstrate that the S295X variant impairs the WNT signaling pathway and results in decreased mineralization (Laine et al., 2013). The S295X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret S295X as a pathogenic variant. |
| Ambry Genetics | RCV001267401 | SCV001445582 | pathogenic | Inborn genetic diseases | 2019-03-22 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000489304 | SCV003441255 | pathogenic | not provided | 2021-12-24 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the WNT1 protein in which other variant(s) (p.Gly303*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Experimental studies have shown that this premature translational stop signal affects WNT1 function (PMID: 23656646). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 50260). This premature translational stop signal has been observed in individual(s) with autosomal recessive osteogenesis imperfecta (PMID: 23499310, 23656646, 29620724). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser295*) in the WNT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 76 amino acid(s) of the WNT1 protein. |
| Fulgent Genetics, |
RCV005007964 | SCV005634650 | likely pathogenic | Osteogenesis imperfecta type 15; OSTEOPOROSIS, EARLY-ONSET, SUSCEPTIBILITY TO | 2024-05-09 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000043495 | SCV000067318 | pathogenic | Osteogenesis imperfecta type 15 | 2013-04-04 | no assertion criteria provided | literature only |