Submissions for variant NM_152564.5(VPS13B):c.11758C>T (p.Arg3920Ter)

gnomAD frequency: 0.00001  dbSNP: rs933746831

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665658	SCV000789814	likely pathogenic	Cohen syndrome	2017-02-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000665658	SCV001591774	pathogenic	Cohen syndrome	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg3945*) in the VPS13B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 78 amino acid(s) of the VPS13B protein. This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 550808). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the VPS13B protein in which other variant(s) (p.Asn3954Lysfs*60) have been determined to be pathogenic (PMID: 20656880). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814211	SCV001755410	likely pathogenic	Abnormality of the nervous system	2021-07-10	criteria provided, single submitter	clinical testing
GeneDx	RCV001813795	SCV002061110	likely pathogenic	not provided	2022-01-06	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 78 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34644002)
CeGaT Center for Human Genetics Tuebingen	RCV001813795	SCV002564016	likely pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing	VPS13B: PM2, PM3, PVS1:Moderate, PP4
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000665658	SCV003799024	likely pathogenic	Cohen syndrome	2022-12-12	criteria provided, single submitter	clinical testing	PVS1, PM2