Submissions for variant NM_152564.5(VPS13B):c.9718dup (p.Met3240fs)

dbSNP: rs886041185

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000359731	SCV000329308	pathogenic	not provided	2021-12-09	criteria provided, single submitter	clinical testing	Observed in a patient with Cohen syndrome who harbors a second VPS13B variant (Aradhya et al., 2012); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22382802)
Ambry Genetics	RCV000624118	SCV000742418	pathogenic	Inborn genetic diseases	2017-04-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409967	SCV001406614	pathogenic	Cohen syndrome	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met3265Asnfs*8) 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). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with VPS13B-related conditions. ClinVar contains an entry for this variant (Variation ID: 279782). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000409967	SCV003801137	likely pathogenic	Cohen syndrome	2023-01-25	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.9793dupA (p.Met3265AsnfsX8) 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 4e-06 in 250664 control chromosomes. c.9793dupA has been reported in the literature in individuals affected with Cohen Syndrome (Aradhya_2012).To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Laboratories classified the variant as pathogenic (n=4) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl	RCV000409967	SCV000485632	likely pathogenic	Cohen syndrome	2016-01-18	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000409967	SCV002082720	pathogenic	Cohen syndrome	2020-08-05	no assertion criteria provided	clinical testing