ClinVar Miner

Submissions for variant NM_001199198.3(TBC1D23):c.1687+2T>A

dbSNP: rs1553731605
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard 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

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