Submissions for variant NM_152564.5(VPS13B):c.11831_11840del (p.Pro3944fs)

dbSNP: rs386834069

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000050056	SCV000699444	likely pathogenic	Cohen syndrome	2022-04-25	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.11906_11915del10 (p.Pro3969LeufsX41) 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. The variant was absent in 251604 control chromosomes (gnomAD). c.11906_11915del10 has been reported in the literature in at-least one compound heterozygous individual affected with Cohen Syndrome (Kolehmainen_2004) and subsequently cited by others (example Seifert_2009, Reuter_2018). These data do not allow firm conclusions about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000050056	SCV001583216	pathogenic	Cohen syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro3969Leufs*41) in the VPS13B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 54 amino acid(s) of the VPS13B protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Cohen syndrome (PMID: 15141358; externalcommunication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56643). This variant disrupts the C-terminus of the VPS13B protein. Other variant(s) that disrupt this region (p.Ser3970Glnfs*22) have been observed in individuals with VPS13B-related conditions (PMID: 16648375). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000050056	SCV000082465	probable-pathogenic	Cohen syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.