Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000168253 | SCV000218924 | likely pathogenic | Familial aplasia of the vermis | 2014-12-03 | criteria provided, single submitter | clinical testing | This sequence change results in a premature translational stop signal in the last exon of the B9D2 mRNA at codon 100 (p.Asp53Leufs*47). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated B9d2 protein. This sequence change has not been published in the literature and is not present in population databases. Two related individuals with Meckel syndrome were found to be homozygous for the missense mutation, p.Ser101Arg (PMID: 21763481). Functional studies of the p.Ser101Arg change suggest that this missense result in abrogated B9d2 binding with Mks1, likely due to the disruption of the B9 domain. This p.Asp53Leufs*47 change is expected to result in a premature termination codon one position prior to the reported p.Ser101Arg. Therefore it is likely to also disrupt the B9 domain. For these reasons, this sequence change has been classified as Likely Pathogenic. |
| Invitae | RCV001850379 | SCV002114350 | pathogenic | Familial aplasia of the vermis; Meckel-Gruber syndrome | 2023-07-14 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Asp53Leufs*47) in the B9D2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 123 amino acid(s) of the B9D2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with B9D2-related conditions. ClinVar contains an entry for this variant (Variation ID: 188273). This variant disrupts a region of the B9D2 protein in which other variant(s) (p.Ser101Arg) have been determined to be pathogenic (PMID: 21763481). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |