Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Broad Center for Mendelian Genomics, |
RCV000508997 | SCV001430746 | likely pathogenic | Pontocerebellar hypoplasia, type 11 | 2020-05-27 | criteria provided, single submitter | research | The homozygous c.1687+2T>A variant in TBC1D23 was identified by our study in 2 Egyptian siblings with pontocerebellar hypoplasia (PMID: 28823706). The presence of this variant in an affected homozygote increases the likelihood that the c.1687+2T>A variant is pathogenic (PMID: 28823706). This variant has also been reported in ClinVar (Variation ID: 440763) but was absent from large population studies. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In vitro functional studies provide some evidence that the c.1687+2T>A variant may slightly impact protein function (PMID: 28823706). However, these types of assays may not accurately represent biological function. While there is some evidence to suggest that loss of function of the TBC1D23 gene is a disease mechanism in autosomal recessive pontocerebellar hypoplasia, this association is not yet strongly established based on the criteria laid out in Tayoun, 2018 (PMID: 30192042). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_Strong, PM2, PS3_Supporting, PM3_Supporting (Richards 2015). |
OMIM | RCV000508997 | SCV000606755 | pathogenic | Pontocerebellar hypoplasia, type 11 | 2017-09-29 | no assertion criteria provided | literature only |