Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000540679 | SCV000630892 | pathogenic | Cohen syndrome | 2023-07-21 | criteria provided, single submitter | clinical testing | Disruption of this splice site has been observed in individual(s) with VPS13B-related disease (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 459251). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 46 of the VPS13B gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in VPS13B are known to be pathogenic (PMID: 15141358, 16648375, 20461111). |
| Greenwood Genetic Center Diagnostic Laboratories, |
RCV001805153 | SCV002051709 | likely pathogenic | not provided | 2021-01-22 | criteria provided, single submitter | clinical testing | PVS1, PM2 |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000540679 | SCV002571849 | likely pathogenic | Cohen syndrome | 2022-08-07 | criteria provided, single submitter | clinical testing | Variant summary: VPS13B c.8521-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' splicing acceptor site. Two predict the variant strengthens an alternate cryptic exonic 3' splice acceptor site. However, these predictions have yet to be confirmed by functional studies. Loss of function variants are associated with Cohen Syndrome in HGMD. The variant was absent in 250248 control chromosomes (gnomAD). To our knowledge, no occurrence of c.8521-1G>T in individuals affected with Cohen Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Counsyl | RCV000540679 | SCV000795215 | likely pathogenic | Cohen syndrome | 2017-11-07 | no assertion criteria provided | clinical testing |