Submissions for variant NM_152564.5(VPS13B):c.11702_11705del (p.Leu3901fs)

dbSNP: rs1161589003

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000627618	SCV000748618	likely pathogenic	not provided	2018-11-08	criteria provided, single submitter	clinical testing	The c.11777_11780delTCAC variant in the VPS13B gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.11777_11780delTCAC variant causes a frameshift starting with codon Leucine 3926, changes this amino acid to a Glutamine residue, and creates a premature Stop codon at position 15 of the new reading frame, denoted p.Leu3926GlnfsX15. This variant is predicted to cause loss of normal protein function through protein truncation. The c.11777_11780delTCAC variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.11777_11780delTCAC as a likely pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001199914	SCV001370682	likely pathogenic	Cohen syndrome	2020-05-18	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.11777_11780delTCAC (p.Leu3926GlnfsX15) 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. A truncation downstream of this position has been classified as likely pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251448 control chromosomes. To our knowledge, no occurrence of c.11777_11780delTCAC in individuals affected with Cohen Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001199914	SCV002243070	pathogenic	Cohen syndrome	2023-10-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu3926Glnfs*15) in the VPS13B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 97 amino acid(s) of the VPS13B protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with VPS13B-related conditions (PMID: 33994118). ClinVar contains an entry for this variant (Variation ID: 524122). This variant disrupts a region of the VPS13B protein in which other variant(s) (p.Pro3969Leufs*41) have been determined to be pathogenic (PMID: 15141358; Invitae). 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001199914	SCV002526696	pathogenic	Cohen syndrome	2022-05-12	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_017890.5:c.5072del._x000D_ Criteria applied: PVS1, PM3, PM2_SUP