Submissions for variant NM_152564.5(VPS13B):c.9331-1G>T

dbSNP: rs386834119

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000050112	SCV000795739	pathogenic	Cohen syndrome	2017-11-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000050112	SCV000918354	pathogenic	Cohen syndrome	2018-10-01	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.9406-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. Two predict the variant strengthens a cryptic 3 acceptor site in exon 52. These predictions were confirmed by at least one publication reporting experimental evidence that this variant affects mRNA splicing. Results showed that the variant lead to the deletion of 16 exonic bases and, thus, a frameshift in mRNA (Hennies 2004). The variant allele was not found in 57574 control chromosomes (gnomAD). c.9406-1G>T has been reported in the literature in multiple individuals affected with Cohen Syndrome in either homozygous or compound heterozygous state (Hennies 2004, Rauch 2006, Duplomb 2014) . These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated a deficiency in Golgi N-glycosylation (Duplomb 2014). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics	RCV000050112	SCV001137688	uncertain significance	Cohen syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000050112	SCV002972345	pathogenic	Cohen syndrome	2022-03-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 15154116). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 56699). Disruption of this splice site has been observed in individuals with Cohen syndrome (PMID: 15154116, 19190672). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 51 of the VPS13B gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
GeneDx	RCV003313035	SCV004012391	pathogenic	not provided	2023-05-10	criteria provided, single submitter	clinical testing	Observed in apparent homozygous state in patients with Cohen syndrome in the literature (Hennies 2004, Rauch 2006) and not observed in homozygous state in controls; Observed with another canonical splice variant in VPS13B, phase (cis or trans) unknown, in a patient with a personal history consistent with Cohen syndrome (El Chehadeh-Djebbar 2013); Canonical splice site variant predicted to result in a null allele 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: 25060287, 19190672, 15154116, 24334764, 16917849, 31825161, 31589614, 29618732, 23188044)
PreventionGenetics, part of Exact Sciences	RCV003415820	SCV004117076	pathogenic	VPS13B-related disorder	2023-06-02	criteria provided, single submitter	clinical testing	The VPS13B c.9331-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported as causative for autosomal recessive Cohen syndrome (described as c.9406-1G>T, Hennies et al. 2004. PubMed ID: 15154116; described as IVS51-1G>T, El Chehadeh-Djebbar et al. 2012. PubMed ID: 23188044; Duplomb et al. 2013. PubMed ID: 24334764). Variants that disrupt the consensus splice acceptor site in VPS13B are expected to be pathogenic. This variant is interpreted as pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000050112	SCV000082522	probable-pathogenic	Cohen syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Natera, Inc.	RCV000050112	SCV001460991	pathogenic	Cohen syndrome	2020-09-16	no assertion criteria provided	clinical testing