ClinVar Miner

Submissions for variant NM_005105.4(RBM8A):c.67+32G>C (rs201779890)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000172898 SCV000331467 pathogenic not provided 2016-01-26 criteria provided, single submitter clinical testing
Fulgent Genetics RCV000023419 SCV000893204 pathogenic Radial aplasia-thrombocytopenia syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneReviews RCV000023419 SCV000086919 pathogenic Radial aplasia-thrombocytopenia syndrome 2016-12-08 no assertion criteria provided literature only
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000172898 SCV000121616 probable-pathogenic not provided no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000172898 SCV000148357 probable-pathogenic not provided no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Invitae RCV000023419 SCV000833764 pathogenic Radial aplasia-thrombocytopenia syndrome 2018-03-02 criteria provided, single submitter clinical testing This sequence change falls in intron 1 of the RBM8A gene. It does not directly change the encoded amino acid sequence of the RBM8A protein. Experimental studies have reported that this variant leads to a partial decrease in RBM8A expression in vitro, possibly by disrupting a transcription factor binding site (PMID: 22366785). This variant has been observed on the opposite chromosome (in trans) from a whole gene deletion of RBM8A in several individuals affected with TAR syndrome (PMID: 22366785). However, it has been reported as homozygous in an unaffected parent (PMID: 22366785) and is common in population databases (rs201779890, ExAC 2.5%), including 2 homozygous unaffected individuals. ClinVar contains an entry for this variant (Variation ID: 30465). In summary, this intronic change has been reported as a hypomorphic variant that partially decreases RBM8A gene expression. This variant causes TAR syndrome when in trans with a null variant; however, homozygous individuals are unaffected. For these reasons, this variant has been classified as Pathogenic (low penetrance).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000023419 SCV000711732 likely pathogenic Radial aplasia-thrombocytopenia syndrome 2016-04-25 criteria provided, single submitter clinical testing The c.67+32G>C variant in RBM8A has been reported in 12 individuals with thrombocytopenia with absent radius (TAR) syndrome, each of whom had a submicroscopic deletion encompassing the RBM8A gene on the second allele (Albers 2012), suggesting that compound heterozygosity for this variant and a loss of function variant in RBM8A is disease causing. In vitro studies demonstrated that this variant may lead to reduced gene expression (Albers 2012); however, these types of assays may not accurately represent biological function. Although this variant has also been identified in 2.5% (100/3994) of Finnish and 0.9% (446/51698) of other European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201779890), no loss of function variants in RBM8A gene have been reported in large population studies, suggesting that compound heterozygosity for the c.67+32G>C variant and a loss of function variant in RBM8A is rare. In summary, although additional studies are required to fully establish its clinical significance, the c.67+32G>C variant is likely pathogenic for TAR syndrome in an autosomal recessive manner.
OMIM RCV000023419 SCV000044710 pathogenic Radial aplasia-thrombocytopenia syndrome 2012-02-26 no assertion criteria provided literature only

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