Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| OMIM | RCV001822091 | SCV002064295 | pathogenic | TCF12-related craniosynostosis | 2022-01-26 | no assertion criteria provided | literature only | |
| Clinical Genomics Laboratory, |
RCV001822091 | SCV004231805 | pathogenic | TCF12-related craniosynostosis | 2021-07-02 | no assertion criteria provided | clinical testing | The c.826-2A>G variant in the TCF12 gene has been previously reported de novo in one individual with bilateral coronal craniosynostosis, left lambdoid craniosynostosis, and dysmorphic features (Paumard-Hernández et al., 2015). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The c.826-2A>G variant alters the canonical acceptor splice site in intron 10, which is predicted to result in abnormal gene splicing. Functional studies of this variant demonstrated the presence of two splicing products – one resulting in a frameshift and one resulting in a deletion of exon 11 (Paumard-Hernández et al., 2015). Computational tools also predict an impact to splicing; however, the accuracy of these computational tools is limited. Heterozygous loss of function is an established mechanism of disease for the TCF12 gene (Sharma et al., 2013; Davis et al., 2020). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the c.826-2A>G variant as pathogenic for autosomal dominant TCF12-related disorder based on the information above. [ACMG evidence codes used: PVS1; PM2; PS2_Supporting; PS3_Supporting] |