Submissions for variant NM_152564.5(VPS13B):c.11620_11623del (p.Ser3876fs)

dbSNP: rs386834066

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000050053	SCV000220195	likely pathogenic	Cohen syndrome	2014-03-27	criteria provided, single submitter	literature only
GeneDx	RCV000627421	SCV000748418	likely pathogenic	not provided	2020-10-08	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 122 amino acids are replaced with 39 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20461111, 23188044)
Invitae	RCV000050053	SCV000947324	pathogenic	Cohen syndrome	2023-05-16	criteria provided, single submitter	clinical testing	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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 56640). This variant is also known as c.11695delAGTG, p.S3899fsX42. This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 20461111, 23188044). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs771209878, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Ser3901Argfs*40) in the VPS13B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 122 amino acid(s) of the VPS13B protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000050053	SCV001774606	pathogenic	Cohen syndrome	2021-07-30	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.11695_11698delAGTG (p.Ser3901ArgfsX40) 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 allele was found at a frequency of 1.6e-05 in 251458 control chromosomes. c.11695_11698delAGTG has been reported in the literature in individuals affected with Cohen Syndrome (example, El Chehadeh-Djebbar_2013, Parri_2010, Duplomb_2019). To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported, although one patient with this variant in a compound heterozygous genotype was included in a study that reported decreased expression of Serpin B1 gene in the neutrophils of patients with Cohen syndrome as well as in VPS13B-deficient cells (Duplomb_2019). 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000050053	SCV000082462	probable-pathogenic	Cohen syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.