Submissions for variant NM_152564.5(VPS13B):c.4745+2T>C

dbSNP: rs386834091

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000050082	SCV000789308	pathogenic	Cohen syndrome	2017-01-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000050082	SCV001360942	pathogenic	Cohen syndrome	2019-11-14	criteria provided, single submitter	clinical testing	Variant summary: VPS13B c.4820+2T>C 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: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251008 control chromosomes (gnomAD). c.4820+2T>C has been reported in the literature in individuals affected with Cohen Syndrome (CS) (Seifert_2008, El Chehadeh-Djebbar_2013). These data indicate that the variant may be associated with disease. A functional study (Duplomb_2014), suggested that Cohen syndrome is associated with major glycosylation defects, and demonstrated protein N-glycosylation alterations in a serum sample, derived from a compound heterozygous patient carrying the variant of interest. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000050082	SCV001589943	pathogenic	Cohen syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 30 of the VPS13B gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individual(s) with Cohen syndrome (PMID: 19006247, 24334764). This variant is also known as IVS30+2T>C. ClinVar contains an entry for this variant (Variation ID: 56669). 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.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000050082	SCV000082491	probable-pathogenic	Cohen syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.