Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000169612 | SCV000221137 | likely pathogenic | Cohen syndrome | 2015-02-13 | criteria provided, single submitter | literature only | |
| Invitae | RCV000169612 | SCV000630862 | pathogenic | Cohen syndrome | 2023-12-31 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Thr3927Lysfs*15) in the VPS13B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 95 amino acid(s) of the VPS13B protein. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individuals with Cohen syndrome (PMID: 16648375). This variant is also known as two separate variants in cis (c.11780delC and c.11783TG>AA). This variant disrupts a region of the VPS13B protein in which other variant(s) (p.Asn3954Lysfs*60) have been determined to be pathogenic (PMID: 20656880). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000169612 | SCV001372250 | pathogenic | Cohen syndrome | 2020-06-16 | criteria provided, single submitter | clinical testing | Variant summary: VPS13B c.11780_11784delinsAGAA (p.Thr3927LysfsX15) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251434 control chromosomes. c.11780_11784delinsAGAA has been reported in the literature in at-least one individual affected with Cohen Syndrome (example, Seifert_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Fulgent Genetics, |
RCV000169612 | SCV002798494 | likely pathogenic | Cohen syndrome | 2022-05-09 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002515202 | SCV003545937 | likely pathogenic | Inborn genetic diseases | 2020-01-15 | criteria provided, single submitter | clinical testing | The alteration results in a premature stop codon: _x000D_ _x000D_ The c.11780_11784delCAGTGinsAGAA (p.T3927Kfs*15) alteration, located in exon 61 (coding exon 60) of the VPS13B gene, results from the deletion of 5 nucleotides and insertion of 4 nucleotides at positions 11780 to 11784, causing a translational frameshift with a predicted alternate stop codon after 15 amino acids. Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of VPS13B, is not expected to trigger nonsense-mediated mRNA decay, and a truncated mutant protein could still be expressed (Maquat, 2004). This alteration impacts the last 82 amino acids of the protein and the exact functional impact of these altered amino acids is unknown at this time; however, other frameshift alterations downstream of this alteration have been reported in the in individuals with a phenotype consistent with Cohen syndrome (Kolehmainen, 2004; El Chehadeh, 2010). The alteration is rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the VPS13B c.11780_11784delCAGTGinsAGAA (p.T3927Kfs*15) alteration was observed in 0.0004% (1/251434) of total alleles studied. The alteration has been observed in affected individuals: _x000D_ _x000D_ This alteration was reported in a patient with suspected Cohen syndrome, whose phenotype included microcephaly, developmental delay, typical facial features, myopia, narrow hands/feet, and neutropenia, and who was heterozygous for a second frameshift alteration (Seifert, 2006). Based on the available evidence, this alteration is classified as likely pathogenic. |