Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000520830 | SCV000622005 | uncertain significance | not provided | 2017-11-01 | criteria provided, single submitter | clinical testing | The c.624 G>A variant in the WNT1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This substitution occurs at a nucleotide position that is conserved across species. Although the c.624 G>A (T208=) variant results in a synonymous amino acid substitution, multiple in-silico splice prediction models predict that c.624 G>A may damage the natural splice donor site in intron 3, which may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. The c.624 G>A variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.624 G>A as a variant of uncertain significance. |
| Labcorp Genetics |
RCV000520830 | SCV004324105 | uncertain significance | not provided | 2023-09-17 | criteria provided, single submitter | clinical testing | This sequence change affects codon 208 of the WNT1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the WNT1 protein. This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 453139). This variant has not been reported in the literature in individuals affected with WNT1-related conditions. This variant is not present in population databases (gnomAD no frequency). |
| Molecular Genetics, |
RCV005250069 | SCV005900342 | uncertain significance | Osteogenesis imperfecta | 2024-09-08 | criteria provided, single submitter | clinical testing | This sequence change is a synonymous (silent) variant altering the last base of exon 3 of WNT1. The results from an in silico splicing predictor (SpliceAI) indicate that this variant may impact splicing by disrupting the donor splice site of intron 3. RNA assays have not been conducted to confirm this prediction. The highest population minor allele frequency in the population database gnomAD v4.1 is 0.0004% (5/1,145,930 alleles) in the European (non-Finnish) population, consistent with recessive disease. To our knowledge, this variant has not been previously reported in the relevant scientific literature or databases. Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP3. |