Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000672425 | SCV000797529 | uncertain significance | Cohen syndrome | 2018-02-05 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000672425 | SCV001581626 | pathogenic | Cohen syndrome | 2023-04-27 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 556421). This variant has not been reported in the literature in individuals affected with VPS13B-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Phe1431Leufs*40) in the VPS13B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in VPS13B are known to be pathogenic (PMID: 15141358, 16648375, 20461111). |
| Ambry Genetics | RCV002331310 | SCV002629544 | pathogenic | Inborn genetic diseases | 2018-01-19 | criteria provided, single submitter | clinical testing | The c.4289dupT pathogenic mutation, located in coding exon 27 of the VPS13B gene, results from a duplication of T at nucleotide position 4289, causing a translational frameshift with a predicted alternate stop codon (p.F1431Lfs*40). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000672425 | SCV002819655 | likely pathogenic | Cohen syndrome | 2022-12-02 | criteria provided, single submitter | clinical testing | Variant summary: VPS13B c.4289dupT (p.Phe1431LeufsX40) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This frameshift variant is located in exon 28, however in the literature an alternative exon (exon 28b) is described as the one which is included in the major, ubiquitously expressed transcript (NM_152564), whereas the transcript containing exon 28 (NM_017890) is reported as expressed mostly in the brain and retina (see e.g. PMIDs: 12730828, 19006247, 35690661). Truncations downstream of this position have been reported in affected individuals (HGMD). The variant was absent in 251300 control chromosomes (gnomAD). To our knowledge, no occurrence of c.4289dupT 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 without evidence for independent evaluation; two labs cited the variant as likely pathogenic, and one lab cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. |