Submissions for variant NM_152564.5(VPS13B):c.3427C>T (p.Arg1143Ter)

gnomAD frequency: 0.00001  dbSNP: rs386834080

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000422497	SCV000520846	pathogenic	not provided	2020-11-06	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 30843084, 32919079, 25525159, 24334764, 20656880, 17990063, 20461111, 31980526, 31589614)
Invitae	RCV000050071	SCV000949743	pathogenic	Cohen syndrome	2023-09-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1143*) 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 (rs386834080, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with VPS13B-related disease (PMID: 17990063, 19006247, 20461111, 20656880). ClinVar contains an entry for this variant (Variation ID: 56658). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000050071	SCV001338009	pathogenic	Cohen syndrome	2020-01-06	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.3427C>T (p.Arg1143X) 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-05 in 251098 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in VPS13B causing Cohen Syndrome (4e-05 vs 0.0025), allowing no conclusion about variant significance. c.3427C>T has been reported in the literature in individuals affected with Cohen Syndrome (Katzaki_2007, El Chehadeh-Djebbar_2010). These data indicate that the variant is associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000050071	SCV002809093	pathogenic	Cohen syndrome	2022-05-12	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000050071	SCV004804746	pathogenic	Cohen syndrome	2024-03-17	criteria provided, single submitter	research
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000050071	SCV005052000	pathogenic	Cohen syndrome	2024-02-01	criteria provided, single submitter	curation
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000050071	SCV000082480	probable-pathogenic	Cohen syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Counsyl	RCV000050071	SCV001132507	likely pathogenic	Cohen syndrome	2015-03-17	no assertion criteria provided	clinical testing