Submissions for variant NM_152564.5(VPS13B):c.2889G>A (p.Trp963Ter)

gnomAD frequency: 0.00002  dbSNP: rs386834078

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000050068	SCV000220163	likely pathogenic	Cohen syndrome	2014-03-14	criteria provided, single submitter	literature only
GeneDx	RCV000269979	SCV000329732	pathogenic	not provided	2022-09-20	criteria provided, single submitter	clinical testing	Identified in patients with Cohen syndrome in published literature (Yu et al., 2013; Kolehmainen et al., 2004); Nonsense 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 (gnomAD); This variant is associated with the following publications: (PMID: 19006247, 29453417, 28832562, 15141358, 33023636, 23352163)
Invitae	RCV000050068	SCV001400461	pathogenic	Cohen syndrome	2023-08-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp963*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Cohen syndrome (PMID: 15141358, 28832562, 29453417). 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: 56655). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000050068	SCV001737807	pathogenic	Cohen syndrome	2021-05-22	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.2889G>A (p.Trp963X) 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 251190 control chromosomes. c.2889G>A has been reported in the literature in individuals affected with Cohen Syndrome and subsequently cited by others (example, Kolehmainen_2004, Yu_2013, Stark_2016, Rafiq_2015, Wang_2020, Dillon_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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, some citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000050068	SCV000082477	probable-pathogenic	Cohen syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Natera, Inc.	RCV000050068	SCV001454822	pathogenic	Cohen syndrome	2020-09-16	no assertion criteria provided	clinical testing