Submissions for variant NM_152564.5(VPS13B):c.2074C>T (p.Arg692Ter)

gnomAD frequency: 0.00001  dbSNP: rs180177356

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000050063	SCV000249402	pathogenic	Cohen syndrome	2015-05-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000050063	SCV000956408	pathogenic	Cohen syndrome	2024-10-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg692*) 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 (rs180177356, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with Cohen syndrome (PMID: 12730828, 16648375, 20656880). ClinVar contains an entry for this variant (Variation ID: 56650). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000050063	SCV001482050	pathogenic	Cohen syndrome	2021-02-25	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.2074C>T (p.Arg692X) 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 8e-06 in 251308 control chromosomes. c.2074C>T has been reported in the literature in individuals affected with Cohen Syndrome (eg. Duplomb_2019, Kolehmainen_2003, Huang_2020). 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. Based on the evidence outlined above, the variant was classified as pathogenic.
New York Genome Center	RCV000050063	SCV001622986	likely pathogenic	Cohen syndrome	2020-06-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000058892	SCV001982934	pathogenic	not provided	2024-09-20	criteria provided, single submitter	clinical testing	Identified in individuals with Cohen syndrome in the published literature (PMID: 16648375, 30843084, 12730828); Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 32919079, 16648375, 12730828, 25525159, 31589614, 20656880, 30843084)
3billion	RCV000050063	SCV005905708	pathogenic	Cohen syndrome	2023-06-09	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 20656880). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000056650 /PMID: 12730828). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000050063	SCV000082472	probable-pathogenic	Cohen syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
SNPedia	RCV000058892	SCV000090413	pathogenic	not provided		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
Natera, Inc.	RCV000050063	SCV001454811	pathogenic	Cohen syndrome	2020-09-16	no assertion criteria provided	clinical testing