Submissions for variant NM_152564.5(VPS13B):c.11239C>T (p.Gln3747Ter)

gnomAD frequency: 0.00002  dbSNP: rs386834061

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415410	SCV000492975	pathogenic	Short stature; Retinal dystrophy; Microcephaly; Progressive visual loss; Intellectual disability; Short foot; Neutropenia; Recurrent aphthous stomatitis; Small hand	2014-11-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000599109	SCV000709905	pathogenic	not provided	2022-11-02	criteria provided, single submitter	clinical testing	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 in large population cohorts (gnomAD); Identified in an individual with Cohen syndrome in published literature (Hennies et al., 2004); This variant is associated with the following publications: (PMID: 25525159, 15154116, 31589614, 33959574, 17990063)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000050048	SCV000918353	pathogenic	Cohen syndrome	2022-10-31	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.11314C>T (p.Gln3772X) 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 251482 control chromosomes (gnomAD). c.11314C>T has been reported in the literature in individuals affected with Cohen Syndrome (Hennies_2004, Katzaki_2007). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000050048	SCV001208927	pathogenic	Cohen syndrome	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln3772*) 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: 15154116, 17990063). ClinVar contains an entry for this variant (Variation ID: 56635). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000050048	SCV002822949	pathogenic	Cohen syndrome	2023-01-20	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000050048	SCV000082457	probable-pathogenic	Cohen syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Counsyl	RCV000050048	SCV001132509	likely pathogenic	Cohen syndrome	2015-07-20	no assertion criteria provided	clinical testing